Accepted Manuscript

Title: Role of GABAB Receptors in Learning and Memory

and Neuropsychological Disorders

Author: Chelcie F. Heaney Jefferson W. Kinney

PII: S0149-7634(15)30172-X
DOI: http://dx.doi.org/doi:10.1016/j.neubiorev.2016.01.007
Reference: NBR 2339

To appear in:

Received date: 10-9-2015

Revised date: 31-12-2015
Accepted date: 21-1-2016

Please cite this article as: Heaney, Chelcie F., Kinney, Jefferson W., Role of GABAB
Receptors in Learning and Memory and Neuropsychological Disorders.Neuroscience
and Biobehavioral Reviews http://dx.doi.org/10.1016/j.neubiorev.2016.01.007

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 Role of GABAB Receptors in Learning and Memory and Neuropsychological

Disorders

Chelcie F. Heaneya, Jefferson W. Kinneyb,c*

a. Center for Learning and Memory, Department of Neuroscience, University of

Texas at Austin, 1 University Station C7000, Austin, TX 78712

b. Behavioral Neuroscience Laboratory, Department of Psychology, University of

Nevada, Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154

c. Nevada Institute of Personalized Medicine, University of Nevada, Las Vegas,

4505 S. Maryland Parkway, Las Vegas, NV 89154

*Corresponding Author – Jefferson W. Kinney, Ph.D.

Jefferson.Kinney@unlv.edu

4505 S Maryland Parkway Box 455030

Las Vegas, NV, 89154

702-895-4766 (voice)

702-895-0195 (fax)
Contents

1. Introduction ....................................................................................................................1
2. Overview of GABA Receptor Mechanisms of Action ..................................................1
3. Role of GABAB Receptors in Oscillatory Neural Activity ............................................4
4. Role of GABAB Receptors in Plasticity and LTP..........................................................5
5. Role of GABAB Receptors in Neurogenesis..................................................................9
6. Effect of GABAB Ligands on Learning and Memory .................................................10
6.1. Passive Avoidance ................................................................................................11
6.2. Active Avoidance .................................................................................................15
6.3. Morris Water Maze ...............................................................................................18
6.4. Radial Arm Maze..................................................................................................21
6.5. Working Memory Tasks .......................................................................................23
6.6. Conditioned Fear ..................................................................................................25
6.7. Conditioned Taste Aversion .................................................................................28
6.8. Conditioned Place Preference ...............................................................................29
6.9. Novel Object Recognition and Location ..............................................................31
6.10. Barnes Maze ........................................................................................................ 33
6.11. Conditioned Space Color Task .............................................................................34
6.12. Social Recognition ................................................................................................34
6.13. General Behavior Conclusions .............................................................................35
7. Changes to GABA and GABAB Markers or Activity Within Clinical Populations ....36
7.1. Schizophrenia .......................................................................................................36
7.2. Epilepsy ................................................................................................................39
7.3. Alzheimer’s Disease .............................................................................................41
7.4. Autism Spectrum Disorders ..................................................................................44
7.5. Mood Disorders ....................................................................................................45
7.6. Addiction ..............................................................................................................46
7.7. General Conclusions Regarding Clinical Populations ..........................................48
8. Concluding Remarks....................................................................................................49
References ..........................................................................................................................51
Highlights:

* GABAB receptors play an important role in neural plasticity

* GABAB receptor ligands can affect hippocampally-dependent behaviors

*GABAB receptors and GABAergic markers are commonly altered within clinical populations that

show altered hippocampally-dependent learning and memory

* GABAB receptors could be a target to help alleviate altered learning and memory symptoms

associated with certain neuropsychological disorders

Abstract

Although it is evident from the literature that altered GABAB receptor function does affect

behavior, these results often do not correspond well. These differences could be due to the task

protocol, animal strain, ligand concentration, or timing of administration utilized. Because several

clinical populations exhibit learning and memory deficits in addition to altered markers of GABA

and the GABAB receptor, it is important to determine whether altered GABAB receptor function

is capable of contributing to the deficits. The aim of this review is to examine the effect of altered

GABAB receptor function on synaptic plasticity as demonstrated by in vitro data, as well as the

effects on performance in learning and memory tasks. Finally, data regarding altered GABA and

GABAB receptor markers within clinical populations will be reviewed. Together, the data agree

that proper functioning of GABAB receptors is crucial for numerous learning and memory tasks

and that targeting this system via pharmaceuticals may benefit several clinical populations.

Keywords: GABAB receptor; learning and memory; cognition; neuropsychological disorders

1
1. Introduction

The process of learning and memory is affected by a number of factors ranging from the

neurotransmitters involved to the particular receptors that are activated by those neurotransmitters.

For instance, it is well documented that N-methyl-D-aspartate (NMDA)-type receptors of

glutamate (the primary excitatory neurotransmitter) play an important role in the encoding of

memories (Tang et al., 1999), whereas metabotropic glutamate receptors appear to modulate the

consolidation of memories (Riedel et al., 2003). Over the years, research has demonstrated that γ-

aminobutyric acid (GABA), the primary inhibitory neurotransmitter of the brain, also plays an

important role in learning and memory. This review will focus on the role of the metabotropic

GABAB receptor in learning and memory, utilizing data from in vitro and in vivo studies; further,

several diseases that exhibit cognitive deficits will be examined for alterations to GABAB

receptors, subunits, markers, and activity to highlight potential therapeutic targets.

2. Overview of GABA Receptor Mechanisms of Action

The ionotropic GABAA receptor provides fast hyperpolarization of postsynaptic neurons

via chloride channels (Enna, 2007), and the effects of altered GABAA receptor function are well

characterized (for review, see Chapouthier and Venault, 2002). In a broad sense, the effects of the

GABAA receptor in a mature brain are straightforward: activation of the receptor leads to

hyperpolarization and decreased likelihood of reaching threshold, whereas deactivation of the

receptor increases a neuron’s likelihood of reaching threshold and firing an action potential. For a

more in depth overview, see Enna, 2007.

The GABAB receptor heterodimer consists of the GABAB1 and GABAB2 subunits. The

GABAB1 subunit has two primary isoforms, GABAB1a and GABAB1b (for discussion of other

2
isoforms, see Jiang et al., 2012). It is generally accepted that the GABAB1a/B2 heterodimer localizes

to presynaptic neurons and GABAB1b/B2 localizes postsynaptically (Foster et al., 2013; Kohl and

Paulsen, 2010; Ladera et al., 2008; Pérez-Garci et al., 2006; Vigot et al., 2006).

Presynaptically, GABAB receptor activation inhibits voltage-gated calcium conductance

via the β and γ subunits of Gi/o G-proteins, which decreases release of vesicular neurotransmitter

(see Fig. 1; Bettler et al., 2004; Couve et al., 2000; Enna, 2007; Padgett and Slesinger, 2010).

Presynaptic GABAB receptor activation can also decrease vesicle recruitment through inhibited

adenylyl cyclase and, thus, decreased cyclic adenosine monophosphate (cAMP) activation (Sakaba

and Neher, 2003). Decreased neurotransmitter release also occurs independently of calcium

(Kabashima et al., 1997), and baclofen, a GABAB receptor agonist, can inhibit vesicle fusion

independent of SNARE, a protein complex that mediates fusion (Hamid et al., 2014; Rost et al.,

2011). Depending on which neurotransmitter is prevented from being released, this effect can be

excitatory or inhibitory to the subsequent postsynaptic neuron. For instance, if an autoreceptor

inhibits the release of GABA onto the postsynaptic neuron, that postsynaptic neuron will have a

greater likelihood of depolarizing. This effect is termed disinhibition because the postsynaptic cell

is being released from the inhibiting effects of GABA. Conversely, if a heteroreceptor inhibits the

release of glutamate, the postsynaptic cell is likely to experience less depolarization due to the

decreased excitatory input.

To hyperpolarize a postsynaptic neuron, GABAB receptors can inhibit adenylyl cyclase and

the cAMP cascade (see Fig. 2; Bettler et al., 2004; Padgett and Slesinger, 2010). Although

activated GABAB receptors decrease cAMP activity, the receptors directly interact with CREB2

to initiate transcription (White et al., 2000). GABAB receptors can also inhibit calcium

conductance (Bettler et al., 2004; Kohl and Paulsen, 2010; Misgeld et al., 1995; Padgett and

3
Slesinger, 2010), or activate inwardly-rectifying potassium (GIRK) channels (Kohl and Paulsen,

2010; Lewohl et al., 1999; Reuveny, 2013). The overall result of these processes produces a slow,

long lasting hyperpolarization of the postsynaptic cell.

Recent studies have elucidated factors that can influence GABAB receptor signaling. For

instance, NMDA receptor activity and GABAB-GIRK signaling appear to be inversely linked

(Sanders et al., 2013). Further, NMDA receptor activation can induce phosphorylation of serine

783 on the GABAB2 receptor subunit or serine 867 on the GABAB1 receptor subunit to promote

endocytosis (Guetg et al., 2010; Terunuma et al., 2014; 2010); however, under conditions that

promote receptor stability, these phosphorylation sites act to maintain GABAB receptor activated-

potassium signaling via GIRK channels (Couve et al., 2002; Kuramoto et al., 2007).

Phosphorylation of serine 892 on the GABAB2 receptor subunit can also increase receptor stability

(Couve et al., 2002). Further, potassium channel tetramerization domains (KCTD) act as auxiliary

subunits (Schwenk et al., 2010), and can alter receptor dynamics (Seddik et al., 2012). In particular,

the KCTD12 subunit can desensitize GABAB receptor-mediated GIRK signaling (Turecek et al.,

2014) and is affected by the phosphorylation of serine 892 (Adelfinger et al., 2014). Recently, the

R7 family of regulator of G-protein signaling proteins (RGS7) and the adaptor protein 14-3-3-eta

also were demonstrated to be capable of altering GABAB-GIRK signaling (Ostrovskaya et al.,

2014; Workman et al., 2015). Based on the variety of potential effects of activated GABAB

receptors, as well as the growing pool of identified GABAB receptor effectors (Schwenk et al.,

2015), it is clear why the role of GABAB receptors in learning and memory may be convoluted

and difficult to unravel.

4
3. Role of GABAB Receptor in Oscillatory Neural Activity

Oscillatory, synchronous activity is theorized to promote synaptic plasticity such as long-

term potentiation (LTP), which in turn is the leading model for the in vivo mechanics of learning

and memory formation (Buzsaki, 1989; Malenka and Bear, 2004). In vitro (Larson et al., 1986)

and in vivo (Greenstein et al., 1988; Pavlides et al., 1988; Stepan et al., 2012) theta frequency (3-

12 Hz) stimulation induces LTP within the hippocampus. This effect appears to require stimulation

during the peak of, but not at the trough of, the theta oscillation (Hölscher et al., 1997; Hyman et

al., 2003; Orr et al., 2001; Pavlides et al., 1988).

GABA plays an important role in regulating oscillations implicated in learning and

memory. Synchronized inhibitory postsynaptic potentials (IPSPs) generated by GABA moderate

gamma (30-100 Hz) (E. O. Mann and Mody, 2010; Traub, 2003; Whittington et al., 1995) and

theta (Gong et al., 2009; Xiao et al., 2012) activity in the hippocampus. These frequencies are

related to the formation of memories both in humans (Jutras and Buffalo, 2010; Rutishauser et al.,

2010; Sederberg et al., 2007) and rodents (Axmacher et al., 2006; Tort et al., 2009). Further, in

vivo theta rhythms correlate with better task performance (Olvera-Cortes et al., 2002), and

blocking theta rhythms impairs learning and memory (Winson, 1978).

The GABAB receptor also helps regulate and modulate oscillatory activity (Kohl and

Paulsen, 2010). For instance, Staubli and colleagues (1999) demonstrated that GABAB receptor

antagonism facilitates learning and memory driven by theta rhythms in vivo. GABAB receptors are

also capable of altering serotonergic-generated hippocampal theta rhythms via disinhibition of

serotonergic neurons within the median raphe nuclei (S. Li et al., 2005). Cooperation between

GABAA and GABAB receptors increases the synchronization of theta activity in the rat occipital

lobe (Xiao et al., 2012). Within the entorhinal cortex, GABAA receptors control the duration of

5
oscillatory activity, and GABAB receptors terminate this synchronous activity (E. O. Mann et al.,

2009).

Activation of hippocampal GABAB receptors is capable of abolishing gamma activity,

whereas the blockade of these receptors decreases the repetitive stimuli necessary to produce

gamma activity (Brown et al., 2007), thus requiring less input to entrain the synchronous activity.

This effect may be due to the activation of postsynaptic GABAB receptors on pyramidal cells

(Patenaude et al., 2003; Scanziani, 2000). In vivo recordings of mobile, awake rats indicate that

intracerebroventricular (ICV) or intrahippocampal infusions of CGP 35348, a GABAB receptor

antagonist, induces theta and increases gamma rhythms (respectively) in CA1 (Leung and Shen,

2007). Although the blockade of GABAB receptors allows for easier entrainment of synchronous

activity, the activation of these receptors is also necessary to regulate the duration of this activity.

Hippocampal GABAB receptor activation also appears to aid in the transition from theta and

gamma activity to sharp wave ripples, which is suggested to be the transition from memory

acquisition to consolidation (Hollnagel et al., 2014). Thus, GABAB receptor activity modulates the

entrainment of, duration of, and transitions between the neural activities associated with the

acquisition and storage of memories.

4. Role of GABAB Receptors in Plasticity and LTP

In addition to LTP, plasticity between neurons can be measured using paired-pulse

stimulation. In the paired-pulse paradigm, a pair of neurons are stimulated twice in rapid

succession, with a set interstimulus interval (ISI), ranging between 25 ms and 400 ms. Typically,

shorter ISIs (25 ms) will inhibit or decrease the effect of the second stimulation, producing less

6
postsynaptic excitation or inhibition; longer ISIs (50-400ms) enhance the effect of the second

stimulus, either through facilitation or disinhibition. These effects, however, are region specific.

Studies clearly indicate that GABAB receptor antagonism in the CA1 enhances synaptic

plasticity and LTP. Application of the antagonists phaclofen or saclofen to postsynaptic GABAB

receptors in the CA1 blocks paired-pulse inhibition of NMDA-mediated excitatory postsynaptic

potentials (EPSPs) (Morrisett et al., 1991); thus, the amount of excitation of the second stimulus

is not decreased, facilitating postsynaptic excitation. Recordings from in vitro and in vivo

experiments show that GABAB receptor antagonism also facilitates LTP (Olpe et al., 1993).

Further, GABAB receptor antagonism facilitates LTP driven by endogenous theta rhythms in vitro

(Staubli et al., 1999). Finally, ICV infusion of CGP 35348 or local hippocampal infusion of another

antagonist, CGP 5699A, reverses paired-pulse depression within CA1 in anesthetized animals

(Leung et al., 2008), again demonstrating that GABAB receptor antagonism enhances postsynaptic

excitatory effects.

Overexpression of both the GABAB1a (Y. Wu et al., 2007) and the GABAB1b (Stewart et

al., 2009) receptor isoforms reduce LTP in the CA1 of transgenic mice. While GABAB1b-/- mice

with intact presynaptic GABAB receptors demonstrate the ability to induce LTP in CA1, GABAB1a-
/-
mice are unable to induce LTP, though they exhibit paired-pulse plasticity (Vigot et al., 2006).

Taken together, these data demonstrate that blocking the function of GABAB receptors within the

CA1 enables plasticity, LTP, and the entrainment of synchronous activity associated with learning.

Conversely, activating GABAB receptors impairs these measures of synaptic plasticity.

In addition to LTP of excitatory currents, the CA1 undergoes calcium- and NMDA-

dependent LTP of GABAB-mediated slow inhibitory postsynaptic currents (sIPSCs); sIPSCs are

required to induce LTP between cortico-CA1 synapses (Remondes and Schuman, 2003). LTP of

7
sIPSCs is suggested to produce a finite window for postsynaptic detection of excitatory inputs,

perhaps to help modulate rhythmic activities (C. S. Huang et al., 2005). For example, rapid

excitatory stimulation induces a sIPSC, which then minimizes the impact of any late-arriving

excitatory inputs. Similarly, high frequency stimulation of the lateral septal nucleus prevents LTP,

an effect that is in part mediated by the activation of GABAB receptors, and which has been

suggested as a regulatory mechanism to prevent an overflow of information from CA3 into other

regions (Hasuo and Akasu, 2001). Thus, GABAB-mediated sIPSCs appear to help transmit only

pertinent information to and within the hippocampus, which suggests that GABAB receptors

moderate plasticity related to learning and memory.

In contrast to the CA1, in vitro activation of GABAB receptors in the dentate gyrus is

necessary for the development of LTP (Burgard and Sarvey, 1991; Mott and D. V. Lewis, 1992;

Mott et al., 1990; 1993). These effects are due to disinhibition – the activated GABAB receptor is

inhibiting other inhibitory processes, producing a net excitatory effect. Further, LTP can be

induced within the dentate gyrus via frequencies reminiscent of endogenous theta (Mott et al.,

1990).

Recordings from anesthetized animals demonstrate that systemically administered

baclofen produces paired-pulse disinhibition of EPSPs in the dentate gyrus, whereas systemic or

ICV administration of CGP 35348 (Brucato et al., 1992; 1995) or systemic administration of the

GABAB receptor antagonist CGP 46381 impairs paired-pulse disinhibition (Brucato et al., 1996).

Similarly, the systemic administration of CGP 46381 decreases the amount of theta-burst

stimulation-induced LTP recorded in the dentate gyrus (Brucato et al., 1996). These facilitatory

effects may be mediated by presynaptic autoreceptors, however, because the activation of

postsynaptic GABAB receptors in the dentate gyrus increases inhibitory current into the neuron

8
(Tao et al., 2013). Blocking the activation of GABAB receptors using the antagonists CGP 55845

or saclofen is usually effective at reversing the facilitatory effect of baclofen (Brown et al., 2007;

Mott and D. V. Lewis, 1992), and antagonists administered alone typically produce no effect on

(Brown et al., 2007) or impair (Brucato et al., 1992; Mott and D. V. Lewis, 1991) LTP and

plasticity. However, recent data demonstrate that saclofen infused into the dentate gyrus increases

population spike amplitudes, in addition to enhancing behavioral LTP (Q.-Y. Liu et al., 2014).

Saclofen can act presynaptically (Harrison et al., 1990), and therefore could be affecting

heteroreceptors. Synaptic plasticity in the dentate gyrus, therefore, appears to rely on the activation

of autoreceptors or the blockade of heteroreceptors.

Recent evidence indicates that glial cells also affect plasticity-related activity (Branchi et

al., 2014; Gemma and Bachstetter, 2013; Reshef et al., 2014; Tremblay et al., 2011). For instance,

microglia help to regulate neurogenesis within the dentate gyrus (Ekdahl, 2012; Gemma and

Bachstetter, 2013; Reshef et al., 2014; Sierra et al., 2010). Additionally, astrocytes and microglia

aid in synapse formation and experience-dependent synapse organization (Diniz et al., 2014; Han

et al., 2013; Paolicelli et al., 2011; Parkhurst et al., 2013; Tremblay et al., 2010). Glial cells utilize

GABA signaling and express GABAB receptors (Losi et al., 2014; Terunuma et al., 2015; Vélez-

Fort et al., 2012; Yoon and C. J. Lee, 2014), and glial GABAergic signaling may help to mediate

plasticity (Serrano et al., 2006). When microglia are strongly activated, learning and memory can

be negatively affected (Yirmiya and Goshen, 2011). The impact on memory could be due to

increased tumor necrosis factor-α (TNF- α) or interleukins (Fiore et al., 2000; Golan et al., 2004;

He et al., 2012; Riazi et al., 2008; Tanaka et al., 2006; 2011). As a population, activated microglia

exhibit more GABAB receptors than resting state microglia (Kuhn et al., 2004). Interestingly,

GABAB receptor activation can help attenuate LPS-induced interleukin-6 and interleukin-12

9
release from activated microglia (Kuhn et al., 2004). It is unclear, however, whether GABAB

receptor activity can help attenuate the activity of other interleukins or TNF- α, or whether this

process would also ameliorate the learning and memory deficits associated with

neuroinflammation.

5. Effect of GABAB Receptors on Neurogenesis

Hippocampal neurogenesis is influenced by a number of factors, including environmental

enrichment and exercise (Kempermann et al., 1997; Nilsson et al., 1999; van Praag et al., 1999b),

and is associated with synaptic plasticity and LTP (Farmer et al., 2004; van Praag et al., 1999a).

Further, neurogenesis is associated with improved long term memory (Bruel-Jungerman et al.,

2005), and learning increases neurogenesis (Gould et al., 1999). When neurogenesis is blocked or

decreased, the effect on memory and synaptic plasticity is deleterious (Jessberger et al., 2009;

Madsen et al., 2003; Raber et al., 2004; Saxe et al., 2006; Shors et al., 2001; Winocur et al., 2006).

The association between neurogenesis and task performance, however, appears to be limited to

hippocampal-dependent tasks only (Shors et al., 2001; Van der Borght et al., 2005).

GABA is a key regulator of neurogenesis (Ge et al., 2007; Markwardt and Overstreet-

Wadiche, 2008; Pontes et al., 2013) and impaired neurogenesis in animal models of Alzheimer’s

disease is related to changes in GABAergic signaling (G. Li et al., 2009; Sun et al., 2009).

Additionally, NMDA receptor antagonists alter GABAergic signaling (Workman et al., 2015;

2013), and increase neurogenesis (Keilhoff et al., 2004; Maekawa et al., 2009). While GABAB

receptors appear to exhibit neurotrophic properties during development (Gaïarsa and Porcher,

2013), active GABAB receptors decrease neurogenesis (Giachino et al., 2014). Conversely, chronic

10
antagonism of GABAB receptors increases ventral hippocampal cell proliferation after a stressful

event (Felice et al., 2012).

Finally, glia are also implicated in regulating neurogenesis. Unchallenged microglia

phagocytose new-born neurons that are apoptotic, demonstrating a maintenance role for microglia

in neurogenesis under non-pathological conditions (Sierra et al., 2010). Mice exposed to stress

exhibit depression-like symptoms, decreased neurogenesis, as well as a decrease in microglia;

when animals are administered compounds to increase microglial proliferation, the depressive-like

symptoms ameliorate and neurogenesis increases (Kreisel et al., 2013). Similarly, in vitro studies

show that removing microglia from cell cultures decreases the survival of neural stem/progenitor

cells (NSPCs), whereas microglia are trophic to NSPCs when added to microglia-depleted cultures

(Nunan et al., 2014). Possibly, based on the data detailed above, there is also an interaction between

GABAB receptors and microglia in neurogenesis.

6. Effect of GABAB Receptors on Learning and Memory

A summary of the ligands described within the following sections can be found in Table 1.

The behavioral data, including ligands, doses, routes of administration, and strains used are also

summarized within tables. While each task utilizes several different brain regions, nearly all

require either the hippocampus, the amygdala, prefrontal cortex, or a combination of the three, and

are discussed. GABAB receptors are present throughout the brain (Bowery et al., 1987; D. C. M.

Chu et al., 1990), and thus, altered receptor activity is expected to affect performance in numerous

behavioral paradigms.

11
6.1. Passive Avoidance

This task administers positive punishment (i.e. footshock) whenever an animal exhibits the

natural tendency to explore its environment. In one version, an animal is placed onto a platform

above an electrified floor; in another version, the animal is placed into a brightly lit chamber next

to a darkened chamber containing an electrified floor. During the acquisition phase, if an animal

steps off the platform or into the darkened chamber, it receives a footshock. Because of its direct

aversiveness, the animals quickly learn to avoid the electrified areas. During the retention phase,

typically 24 hours after the acquisition phase, the animal is placed back into the apparatus, either

on the platform or in the lit chamber. Latency to either step down from the platform or step through

to the darkened chamber is recorded. When compared to the control group, performance is

considered impaired if the animal has a shorter latency, or enhanced if the animal has a longer

latency, to step down or step through.

Passive avoidance requires several brain regions for proper performance. Task acquisition

requires both the ventral and dorsal hippocampus (Ambrogi Lorenzini et al., 1997; 1996) and the

basal forebrain (Miyamoto et al., 1985; Page et al., 1991). Consolidation of this task utilizes the

hippocampus, amygdala, anterior cingulate cortex, the medial prefrontal cortex, and the nucleus

basalis (Ambrogi Lorenzini et al., 1997; 1996; 1994; Bucherelli et al., 1992; M. Kim and

McGaugh, 1992; Wilensky et al., 2000; Zhang et al., 2011). Based on work with transgenic

animals, acquisition of this task also appears to need functional GABAB receptors (Kasten and

Boehm, 2015). Knockouts lacking either the GABAB1a or GABAB1b receptor isoform do not show

any behavioral deficits (Jacobson et al., 2007), suggesting that the presence of either presynaptic

or postsynaptic receptors are sufficient for task acquisition. However, mice lacking either all

12
GABAB1 or GABAB2 receptor subunits exhibit impaired task performance (Gassmann et al., 2004;

Schuler et al., 2001). Table 2 provides a summary of the data below.

Systemic administration of baclofen impairs performance in C57BL/6J (Castellano et al.,

1993; Dubrovina and Zinov'ev, 2008) CD1 (Castellano et al., 1989; Cryan et al., 2004), and OF1

mice (Cryan et al., 2004), as well as in Wistar rats (Nakagawa et al., 1993). However, in DBA/2

(Castellano et al., 1993) and ICRC mice (Saha et al., 1993) baclofen improves passive avoidance

performance. One explanation for these results could be the basal amounts of NMDA NR1 receptor

subunit and GABAB2 receptor subunit proteins in the hippocampus for each mouse strain.

Compared to C57BL/6J mice, naïve DBA/2 mice exhibit decreased levels of NR1 and increased

levels of GABAB2 (Sunyer et al., 2009a). However, CD1 and OF1 also have increased hippocampal

GABAB2 protein levels compared to C57BL/6J mice. If, as these data suggest, variances in receptor

quantity can influence behavioral outcomes, it would be expected that treatment with an antagonist

would produce the opposite behavioral results compared to agonist treatment. Indeed, for

C57BL/6J and DBA/2 mice, this hypothesis holds true (Castellano et al., 1989). However, CGP

35348 also improves performance in ICRC mice (Saha et al., 1993).

Several studies report no behavioral changes in response to baclofen administration. Some

of these null results could be due to drug administration being too early (several days pre-training,

Zarrindast et al., 2008) or too late (one to two hours post-training, Castellano et al., 1989;

Swartzwelder et al., 1987) to see an effect. In other instances, the concentration of baclofen could

be too low (Car and Wiśniewska, 2006; Car and Wiśniewski, 1998; Cryan et al., 2004; Kuziemka-

Leska et al., 1999; Zarrindast et al., 1998). To this point, however, systemic baclofen administered

as low as 0.25 mg/kg can disrupt passive avoidance acquisition in rats (Car and Michaluk, 2012;

Car and Wiśniewska, 2006), but this concentration may be too low to affect consolidation or recall

13
(Car and Wiśniewska, 2006; Car and Wiśniewski, 1998; Cryan et al., 2004; Kuziemka-Leska et

al., 1999). The acquisition effects may be baclofen-specific because administration of the positive

allosteric modulator (PAM) GS 39783 does not produce any behavioral alterations (Cryan et al.,

2004). Interestingly, lower concentrations (less than 5 mg/kg) of systemic baclofen impair

consolidation up to thirty minutes post-training (Zarrindast et al., 2004a), whereas higher

concentrations (5 mg/kg and above) do not seem effective even after ten minutes post-training

(Swartzwelder et al., 1987). In the few instances when baclofen improves passive avoidance

performance, high concentrations of baclofen are utilized immediately post-training (Castellano et

al., 1993; Georgiev et al., 1988; Saha et al., 1993). In order to affect consolidation, a lower

concentration of systemic baclofen may need to induce a subtler alteration when not administered

immediately; alternatively, higher concentrations may improve consolidation when administered

directly after training.

Given that baclofen can affect both acquisition and consolidation of this task, it would be

expected that GABAB receptor antagonists also produce some effect. In the instances an antagonist

is used to investigate task acquisition, a positive effect is found only in studies that administered

an antagonist repeatedly and systemically prior to training (Getova and Dimitrova, 2007; Yu et al.,

1997), or specifically when the drug is administered orally (Mondadori et al., 1993). When not

administered systemically (Zarrindast et al., 2008) or only administered once (Dubrovina and

Zinov'ev, 2008; Zarrindast et al., 1998), no effect is observed. To date, Zarrindast et al. (2008) is

the only group to investigate whether CGP 35348 can alter passive avoidance acquisition, however

they only pretreat with the ligand and do not actually administer it on the day of training. In the

other studies, systemic phaclofen is used; while some studies do demonstrate that systemic

14
phaclofen can affect behavior, phaclofen may not cross the blood-brain barrier very well (De Luca

and Massotti, 1990), and may be ineffectual in this particular task.

Administration of GABAB receptor antagonists immediately post-training, by and large,

improves passive avoidance performance (Castellano et al., 1993; Mondadori et al., 1993; 1996b;

Saha et al., 1993; Zarrindast et al., 2004b). Genkova-Papazova et al. (2000), however, do not

report an improvement with intraperitoneal administration of the antagonist CGP 36742; this result

could be based on the behavioral outcome they report. Most other studies report on the latencies

or number of errors, whereas Genkova-Papazova et al. (2000) report the percent of correct

responses, and thus, possibly are reporting a ceiling effect. As mentioned in the section above,

DBA/2 mice exhibit impaired task performance after treatment with CGP 35348 (Castellano et al.,

1993), but this may be related to the basal amount of GABAB receptors these mice have.

Interestingly, Zarrindast et al. (2002) report that post-training infusions of CGP 35348 into the

CA1 impairs performance, but post-training ICV administration improves performance (Zarrindast

et al., 2004b). These studies also show that post-training intra-CA1 or ICV infusions of baclofen

impair performance. Together, these data could suggest that the hippocampus needs to interact

with other structures (and in particular, the amygdala, Huff and Rudy, 2004) in order to improve

performance, otherwise altered function of just the hippocampus, regardless of inhibition or

disinhibition, will impair passive avoidance performance.

Together these studies suggest that GABAB receptor activation is detrimental to the

consolidation of this task, whereas blockade of these receptors will improve acquisition,

consolidation, and task performance. However, there appears to be a temporal constraint to the

deleterious effect of receptor activation on consolidation. Ligand concentration and strain of mouse

are also important considerations.

15
6.2. Active Avoidance

Like passive avoidance, the active avoidance paradigm requires animals to learn an

association between a footshock and a given stimulus. Whereas passive avoidance required the

animal to avoid moving or performing a natural behavior (e.g. exploration of a dark chamber),

active avoidance requires an action to escape the footshock. This task usually occurs in a two-

chamber shuttle box; whenever a light or tone (conditioned stimulus) turns on, the animal is given

a set amount of time (usually less than 10 s) to exit their current chamber to avoid a footshock that

turns on once the conditioned stimulus terminates. In the “one-way” version of this task, there is a

specific chamber in which an animal will never receive a footshock, and is thus considered the

“safe chamber.” In the “two-way” version, there is not a specific chamber associated with the

footshock; instead, the conditioned stimulus is utilized to signify the onset of the footshock.

Performance in this task is measured in latency to avoid (enter the other chamber before the

termination of the conditioned stimulus) or escape (enter the other chamber after the onset of

footshock) the footshock, with shorter latencies indicating acquisition of the association between

the conditioned stimulus and the footshock.

Acquisition of this task is is impaired by lesioning the basal forebrain (one-way, Miyamoto

et al., 1985), amygdala (two-way, Eclancher and Karli, 1980), or hippocampus (one-way, Olton

and Isaacson, 1968); or by blocking dopamine receptors in the nucleus accumbens or dorsolateral

striatum (two-way, Boschen et al., 2011). Acquisition is improved in the two-way paradigm with

lesions to the hippocampus (Jarrard, 1976; Olton and Isaacson, 1968) or with lesions to, or

stimulation of, the nucleus basalis (Dokla and Thal, 1989; Montero-Pastor et al., 2004).

Consolidation is impaired by blocking dopamine receptors in the nucleus accumbens (two-way,

16
Boschen et al., 2011), and marginally decreased by electrical stimulation of the nucleus basalis

(two-way, Montero-Pastor et al., 2004).

Unlike the above studies that investigated passive avoidance, many more studies focus on

the effect of GABAB receptor antagonism (compared to agonism) in the active avoidance task (see

Table 3 for a summary of these results). Getova et al. (1998; 1997) tested several different

antagonists (CGP 36742, CGP 55845, CGP 56433, CGP 61344, CGP 62349, and CGP 71982). In

these studies, the ligands were administered systemically and prior to all two-way active avoidance

training sessions, as well as the retention test. Therefore, it is difficult to determine whether these

particular ligands affected acquisition or recall of this task. In any case, the majority of these

antagonists (CGP 55845, CGP 56433, CGP 61344, CGP 62349, and CGP 71982) improved

performance; one ligand, CGP 36742, impaired performance (Getova et al., 1997; Getova and

Bowery, 1998). However, after two weeks of pre-treatment, CGP 36742 improved performance

(one-way, Yu et al., 1997), and therefore chronic systemic administration of this particular ligand

may be necessary in order to produce an effect. In another series of experiments, Getova and

Dimitrova (2007) tested the chronic systemic administration of several antagonists (CGP 63360a,

CGP 76290a, and CGP 76291a) in two-way active avoidance. This administration schedule

produces improved performance for CGP 63360a and CGP 76290a, but CGP 76291a did not affect

acquisition.

Another study found no effect of CGP 36742 when it was administered post-training (two-

way, Genkova-Papazova et al., 2000). As mentioned above, however, Genoka-Papazova et al.

(2000) list percent of correct responses, and could be reporting ceiling effects. Post-training Intra-

cingulate infusion of saclofen, however, does improve consolidation (Farr et al., 2000). Sharma

and Kulkarni (1993) administered CGP 35348 (which was fairly successful at improving

17
consolidation of the passive avoidance task) prior to training in the one-way avoidance protocol

and found no effect of the ligand.

Systemic pre-training administration of baclofen does alter active avoidance acquisition,

however it is unclear in which direction. Stuchlik and Vales (2009) utilized a range of baclofen

doses (3.5 – 6 mg/kg) that impaired one-way acquisition in rats, but Sharma and Kulkarni (1993)

found that 0.5 mg/kg improved one-way acquisition in mice. However, Kuziemka-Leska et al.

(1999) did not find an effect of 0.75 mg/kg of baclofen on two-way acquisition in rats. As with

passive avoidance, it is possible that the concentration of baclofen differentially alters

performance. These studies utilized different strains and species, and thus it is possible each has

different basal levels of the GABAB receptor. Possibly that the training protocol (one-way vs two-

way) may also affect the results.

Similarly, the effect of baclofen on consolidation is also undetermined. Systemic

administration improves consolidation in rats (two-way, Georgiev et al., 1988), but intra-cingulate

infusions post-training impairs performance in mice (one-way, Farr et al., 2000). Based on the

studies described above, hippocampal lesions improve task acquisition. Possibly, the reverse is

true for consolidation, which improves with less inhibition in the cingulate cortex. Finally, Fogel

et al. (2010) demonstrate that disrupting rodent REM sleep with baclofen impairs consolidation of

the two-way protocol.

Active avoidance appears to be sensitive to GABAB receptor blockade when a ligand is

chronically pre-treated or administered prior to both training and recall. Activation of GABAB

receptors also appears to affect acquisition, although in no clear direction. Consolidation may

require less GABAB receptor-mediated inhibition of the cingulate cortex, and REM sleep may be

necessary.

18
6.3. Morris Water Maze (MWM)

The MWM is a spatial navigation task that requires animals to utilize extra-maze cues to

locate a hidden platform that is submerged under opaque water. Rodents are good, yet reluctant,

swimmers and are motivated to escape the water as quickly as possible. The task is usually

conducted over several days using a circular tank virtually divided into quadrants. Time taken to

locate the hidden platform (latency) and performance on a probe trial are the main measures of

task comprehension. The faster an animal finds the hidden platform, the more accurately it knows

the spatial location. Probe trials are usually conducted 24 hours after the last training session.

During the probe trial, the hidden platform is removed from the tank and the animals are allowed

a free swim period; the amount of time spent in the quadrant of the platform’s previous location is

measured. Thus, the more time spent in the quadrant where the platform used to be located, as

compared to the other quadrants, the better animal has learned the task. Impaired performance is

marked by increased latencies compared to controls to find the hidden platform, as well as by equal

time spent in all quadrants during the probe trial.

The hippocampus is one of the primary regions involved in both task acquisition and

consolidation (Florian and Roullet, 2004; Morris et al., 1982; Redish and Touretzky, 1998;

Sutherland et al., 1982; 1983). The cerebellum and medial septum also contribute to the acquisition

of this task (Gandhi et al., 2000; Rashidy-Pour et al., 1996). Consolidation of this task relies on

the perforant pathway, medial frontal cortex, and the caudate putamen, as well (Remondes and

Schuman, 2004; Setlow and McGaugh, 1999; Sutherland et al., 1982). Further, the performance

of RGS7 knockouts indicates that RGS7, which regulates the interaction between GABAB

receptors and GIRK channels, is also necessary to acquire this task (Ostrovskaya et al., 2014).

Table 4 summarizes the effect of altered GABAB receptor function on performance in this task.

19
 In most instances, pre-training administration of baclofen, whether systemic (McNamara

and Skelton, 1996; Nakagawa et al., 1995; Nakagawa and Takashima, 1997) or intra-hippocampal

or intra-entorhinal (Arolfo et al., 1998; P.-Y. Deng et al., 2009), impairs task acquisition. Car and

Michaluk (2012) and Li et al. (2014) report no effect of baclofen administration. As reviewed

above, 0.25 mg/kg of baclofen impairs passive avoidance acquisition, but this concentration may

be too low to produce any behavioral differences in the MWM (Car and Michaluk, 2012).

Additionally, the lowest reported concentration of systemic baclofen to affect MWM performance

is 2 mg/kg (Nakagawa et al., 1995). Li et al. (2014) administered baclofen the night before testing

the animals in the MWM; thus, the window to detect any behavioral changes due to baclofen may

be missed.

Interestingly, to the best of the authors’ knowledge, no studies have investigated the effect

of baclofen on MWM task consolidation, and only one has examined the effect of an antagonist.

When infused into the CA1, CGP 35348 has no effect on task consolidation or recall (Shahrzad

and Nasser, 2015); however, the concentrations utilized, (2.5 and 5 ug) may be too small to produce

an effect. For instance, passive avoidance consolidation is affected by CGP 35348 infused at

concentrations of 10 ug or higher only (Zarrindast et al., 2004b; 2002). These lower concentrations,

however, are effective at improving MWM acquisition (Shahrzad and Nasser, 2015). Though, task

acquisition is not affected by intra-entorhinal infusion of CGP 55845 (P.-Y. Deng et al., 2009).

As with passive avoidance, there are differential effects to a single ligand based on the

strain of mouse utilized. For instance, CGP 36742 has no effect on task acquisition in BALB/c and

CF1 mice (Sunyer et al., 2007) or Wistar rats (Nakagawa and Takashima, 1997); C57BL/6J and

OF1 mice perform better than controls when treated with the antagonist (Sunyer et al., 2007;

2009b), and CD1 and DBA/2 mice demonstrate impaired task performance (Sunyer et al., 2007).

20
While there are differences in basal receptor levels in the hippocampus, there are also differences

in how well these strains acquire the task without any drug manipulations. BALB/c mice have

difficulty learning this task, and DBA/2 mice tend to perform worse than C57BL/6J (Upchurch

and Wehner, 1988). As described above, DBA/2 mice have more hippocampal GABAB2 and fewer

NR1 receptor subunits than C57BL/6J, and treatment with CGP 36742 may have a larger

disinhibitory effect in this strain.

When administered systemically to female rats, CGP 46381 impairs performance as

measured by latency to find the hidden platform (Brucato et al., 1996). The protocol utilized in

this study, however, may influence the results. The rats were only trained for one day, and then

immediately given a probe trial after the last training trial. During the training trials, the animals

were released from the same quadrant each time, making the task less dependent on extra-maze

spatial cues. Furthermore, the animals were not impaired on the probe trial, indicating they spent

more time in the quadrant where the platform had been located as compared to the other quadrants.

What is more, the ligand utilized in this study is not commonly used in vivo and its effects cannot

be compared to other studies. However, CGP 46381 is rather potent compared to other antagonists

(Olpe et al., 1993); it is, therefore, possible that this antagonist is binding to both autoreceptors

and postsynaptic receptors to produce the memory impairment.

Together, these data indicate that too much GABAB receptor activation impairs

performance in the MWM, whereas blocking these receptors may improve performance. Although

there are more data based on systemic administration, activating GABAB receptors within the

entorhinal cortex appears to be more detrimental to task acquisition than receptor blockade.

Further, acquisition appears to be bidirectionally affected by GABAB receptor activity within CA1.

The results based on systemic GABAB receptor antagonism, however, are possibly skewed based

21
on the differential strain effects. This discrepancy could be addressed by administering baclofen

to the strains that exhibited impaired performance due to antagonist treatment. Possibly, baclofen

would improve their performance, as suggested by just such an occurrence as reviewed above in

the passive avoidance section. If this hypothesis holds true, these data would indicate that altering

GABAB receptor activity in the appropriate direction (based on basal quantities) is beneficial to

certain learning and memory paradigms.

6.4. Radial Arm Maze (RAM)

In this spatial learning and memory task, animals are placed into the center of a maze with

(usually eight) arms radiating outward in spokes and are required to find a food reward at the end

of the arms. Performance in this task is measured by latency to find all of the food rewards, and

number of errors committed. Depending on the protocol being used, these errors can be working

or reference memory errors. A working memory error occurs if an animal re-enters an arm it has

previously been down. A simple version of this task requires the animals to obtain food rewards

from all eight baited arms, and animals can only commit working memory errors. A harder

variation calls for half of the arms to be baited and the other half to be unbaited; in this version, a

reference memory error would be an entry into an arm that has never contained a food reward. A

delay can be introduced to make the task even more difficult. In this version of the task, half of the

arms are blocked and the other half remain open and baited. The animals are allowed to enter all

four of the unblocked arms before being removed from the maze for a set period of time. After this

delay, the animal is returned to the maze, which now has all of the arms open, but only the

previously blocked arms are baited.

22
 As a spatial navigation task, the hippocampus is necessary for radial arm maze task

acquisition (Winocur, 1982) and consolidation (Jarrard, 1978). Alterations to the medial septum

and the basal forebrain also affect task acquisition (Chrobak and Napier, 2002; Mitchell et al.,

1982). When animals are trained using the delay paradigm, the prefrontal cortex becomes

necessary and interacts with the hippocampus (Floresco et al., 1997; Porter et al., 2000). However,

if animals are trained using the non-delay protocol, the hippocampus interacts with the nucleus

accumbens (Floresco et al., 1997).

The data below are summarized in Table 5. Intra-septal administration of baclofen impairs

consolidation (Stackman and Walsh, 1994) of the difficult (delay) version of the task. CGP 35348

and CGP 36742 improve acquisition and consolidation of the delay paradigm in male rats (Helm

et al., 2005; Staubli et al., 1999). Overexpression of either the GABAB1a (Y. Wu et al., 2007) or

the GABAB1b (Stewart et al., 2009) receptor isoform impairs performance in the baited/unbaited

version of this task, and these transgenic animals demonstrate more working memory errors

compared to wild-type littermates. However, neither CGP 35348 nor CGP 46381 affected

acquisition or recall (respectively) in male or female rats in the baited/unbaited protocol (Brucato

et al., 1996; Chan et al., 2006). In the simplest version where all arms are baited, lower

concentrations of systemically administered baclofen can either impair (1.0 mg/kg) or improve

(0.25 mg/kg) task recall in female Sprague-Dawley rats (Levin et al., 2004). Recall is not affected

by higher concentrations of systemic baclofen in male Fischer rats (1.25 and 2.5 mg/kg, Sidel et

al., 1988) yet is negatively affected in male CD1 mice (2 and 4 mg/kg, Carletti et al., 1993).

Further, CGP 3472 improves recall in male CD1 mice (Carletti et al., 1993), but CGP 46381 has

no effect on female Sprague-Dawley rats (Brucato et al., 1996).

23
 Together, these data do suggest an effect of GABAB receptor activity on performance in

the radial arm maze. However, there are reported sex differences in task performance (Bimonte et

al., 2000; Luine and Rodriguez, 1994; Seymoure et al., 1996; Williams et al., 1990), as well as in

quantity of GABAB receptors in the hypothalamus (Bianchi et al., 2005). In addition to these sex

and receptor differences, it is possible that altering GABAB receptor activity may differentially

affect hippocampal, nucleus accumbens, or prefrontal cortex functionality. However, given that

most of these studies administered ligands systemically, it is difficult to piece together the

contribution of GABAB receptors within these regions. Further, based on the differing

concentration effects of baclofen, possibly too much or too little activation of the GABAB receptor

can also influence performance.

6.5. Working Memory Tasks

Spontaneous alternation measures working memory and can be tested with a T, Y, or

double Y maze. In each apparatus, the choice to visit a new arm or return to a previously explored

arm is measured. Performance is measured in terms of the percentage of alternated arm choices

compared to total number of arm entries. A higher percentage of alternations is indicative of better

working memory. Task performance is modulated by several brain regions, including the

hippocampus (Johnson et al., 1977; Means et al., 1971), medial septum (Clody and Carlton, 1969;

Douglas and Raphelson, 1966), basal forebrain (Murray and Fibiger, 1986), prefrontal cortex

(Divac et al., 1975), medial thalamus (Weis and Means, 1980), and basal ganglia (Divac et al.,

1975). Both GABAB1 receptor isoforms appear to be necessary for appropriate task performance

since GABAB1a and GABAB1b receptor knockouts are impaired in this task (Jacobson et al., 2007).

Further, hippocampal protein levels of both GABAB1 receptor isoforms are increased in mice

24
trained in this task compared to untrained mice (Falsafi et al., 2015). Table 6 summarizes the

behavioral data discussed below.

A variety of studies have investigated the effect of altered GABAB receptor function within

the regions implicated in working memory task performance. Infusions of baclofen into the medial

septum (Erickson et al., 2006), basal forebrain (DeSousa et al., 1994), or medial thalamus

(Romanides et al., 1999) impairs working memory performance; baclofen infused into the ventral

tegmental area, however, does not affect behavior (Romanides et al., 1999). GABAB receptor

antagonists infused into either the basal forebrain (DeSousa et al., 1994) or the medial prefrontal

cortex (Bañuelos et al., 2014) do not affect performance. However, performance improves when

saclofen is infused into the dentate gyrus (Q.-Y. Liu et al., 2014). Systemic administration of CGP

55845 has been shown to impair working memory (Bañuelos et al., 2014); however,

Kleschevnikov et al. (2012a) found no effect, possibly due to administering the ligand two to three

hours prior to testing. These data demonstrate the importance of this receptor system for this

particular task.

Another working memory task is the delayed matching-to-position task (DMTP). In this

task, animals are first trained to poke their noses into a food magazine for a reward. Once learned,

the animals are then trained to press a lever in order for the nose-poke to result in the presentation

of the reward in the food magazine. In the next phase, animals must complete the lever-press-nose-

poke behavior (sample phase) in order to be presented immediately with two lever choices – one

new lever and the lever they originally pressed (choice phase). The animals must then learn to

press the lever they were originally presented with in order to receive the food reward. In the final

stage of training, a temporal delay is introduced between the sample and choice phases. Testing

typically begins after animals have reached an accuracy criterion for these behaviors. Interestingly,

25
systemic administration of baclofen or phaclofen improves performance in this task (Escher and

Mittleman, 2004). What is more, this study utilized female C57BL/6J and DBA/2 mice and both

showed task improvement in response to ligand treatment. These two strains typically show

opposite behavioral effects to GABAB receptor ligand treatment (see above behavior sections).

Based on the intra-cerebral administration studies, most of the brain regions that have been

identified to influence task performance appear to be sensitive to altered GABAB receptor activity.

Possibly, these regions are differentially affected by altered receptor activity (like the basal

forebrain), which could explain the differing results observed in the studies that utilized systemic

administration. Further, possible sex, strain, and ligand mechanism differences could give rise to

those different results.

6.6. Conditioned Fear

Conditioned fear can be induced utilizing numerous protocol variations. Generally, a tone

is paired with a footshock in a specific environment, and the animal is then tested for the strength

of the association between the tone and footshock (cued association), as well as the original

environment and the footshock (contextual association). If the associations were adequately made,

an animal will freeze to the presentation of the tone, even if it is presented in a novel environment;

furthermore, the animal should freeze when it is placed back into the original training environment,

indicating that it learned the contextual association. Further, extinction of these associations can

be measured. Extinction occurs when the animal is repeatedly presented with either the tone or

original context without any further footshocks. With repeated exposure, the animal should freeze

less. Impaired performance in this task is marked by a reduction of freezing behavior to either the

26
tone or the original training environment. Impaired extinction is exhibited by a lack of decreased

freezing with repeated exposure to the tone or original context.

The brain regions associated with fear conditioning are well mapped. When the cue and

footshock occur together (delay protocol), cued associations are routed from the auditory thalamus

to the lateral amygdala and then on to the central amygdala and brainstem (LeDoux, 2000; Phillips

and LeDoux, 1992). Contextual associations require both the hippocampus and the amygdala (J.

J. Kim and Fanselow, 1992; Phillips and LeDoux, 1992). Contextual information from the

hippocampus is projected to the basal nucleus, and then to the central amygdala and brainstem

(LeDoux, 2000). This task can be made more difficult by adding a temporal delay between the

offset of the tone and onset of the footshock (trace protocol). In this version of the task, the

hippocampus also becomes involved in learning the cued association (Chowdhury et al., 2005;

Moyer et al., 1990). Extinction involves the ventral medial prefrontal cortex, the amygdala, and

the hippocampus (Morgan and LeDoux, 1995; Sotres-Bayon et al., 2006).

GABAB1a knockout mice are able to acquire a cued association (see Table 7); however,

they also exhibit generalized fear to both a neutral tone and neutral context unassociated with the

footshock (Cullen et al., 2014; Shaban et al., 2006). GABAB1b knockout mice are unable to learn

the association and thus, do not freeze in response to the presentation of the tone after the

acquisition phase (Shaban et al., 2006). Transgenic mice that display increased postsynaptic

GABAB receptor stability display decreased freezing in the original environment (Terunuma et al.,

2014), and mice lacking RGS7 also demonstrate impaired contextual fear conditioning

(Ostrovskaya et al., 2014).

The effect of systemically administered baclofen on conditioned fear is unclear. Baclofen

may not affect acquisition of the trace protocol (Heaney et al., 2012), but it might enhance

27
acquisition of the delay protocol (X. Li et al., 2013). Further, systemic baclofen impairs

consolidation of the delay protocol (Castellano et al., 1989). Systemic baclofen also appears to

impair the extinction of the contextual association after the trace protocol (Heaney et al., 2012). In

other instances, baclofen does not affect task performance (administered two hours post-training,

Castellano et al., 1989; administered 30 minutes pre-trining, X. Li et al., 2015), and Li et al. (2015)

suggest that the observed effects may be due to baclofen-induced sedation. For instance, while

baclofen administration did increase freezing to both the cue and context, baclofen-treated animals

also froze more in the novel environment used to test the cued association (X. Li et al., 2013). In

order to address this concern, they tested the PAM BHF 177, which did result in decreased

contextual freezing (X. Li et al., 2013), but was not later replicated (X. Li et al., 2015). Further, a

different agonist, CGP 44532 also did not produce any effects on the acquisition of conditioned

fear (X. Li et al., 2015). Finally, neither CGP 55845 nor phaclofen affect task performance (Heaney

et al., 2012; Kleschevnikov et al., 2012a).

Based on the transgenic studies, these data suggest an important role for the presynaptic

GABAB1a receptor isoform in discriminating between both cued and contextually conditioned

stimuli. The postsynaptic GABAB1b receptor isoform and postsynaptic signaling appear important

in acquiring contextual information. While the data are not necessarily as clear for the ligand

studies, it does seem that GABAB receptors may affect extinction and, therefore, may play a role

in updating previously acquired memories. Possibly, the results from the ligand studies may be so

variable simply because they all utilized systemic administration, different schedules of

administration, and different protocols (trace versus delay). As detailed above, different

concentrations of baclofen have different behavioral effects depending on when it is administered.

28
Altogether, however, these data do indicate a role for GABAB receptors in conditioned fear, and

more data need to be collected before that exact role is elucidated.

6.7. Conditioned Taste Aversion

Conditioned taste aversion occurs when a novel, palatable flavor (usually saccharine water)

is introduced to animals that are later injected with a compound that induces an ill feeling. This

test measures how well animals acquire the aversive association between the sweetened water and

feeling ill, as indicated by the amount of the sweetened water ingested upon re-exposure. Impaired

performance is indicated by more of the sweetened water being ingested compared to controls.

Brain regions implicated in the acquisition of conditioned taste aversion include the parabrachial

nucleus of the pons (Reilly, 1999; Yamamoto and Fujimoto, 1991; Yamamoto et al., 1995), medial

thalamus (Yamamoto et al., 1995; Yamamoto and Fujimoto, 1991), insular cortex (Bermudez-

Rattoni and McGaugh, 1991; Braun et al., 1982), and amygdala (Gallo et al., 1992; Roldan and

Bures, 1994; Yamamoto et al., 1995; Yamamoto and Fujimoto, 1991). Consolidation of

conditioned taste aversion appears to modulated by the amygdala (Bahar et al., 2004), and

extinction is affected by altered amygdala, hippocampus, and insular cortex activity (Bahar et al.,

2004; Berman and Dudai, 2001; Reilly et al., 1993).

GABAB1a knockouts are unable to acquire the aversion, but GABAB1b knockouts

demonstrate an impaired ability to extinguish the acquired association (Jacobson et al., 2006).

Systemic administration of either 2 or 3 mg/kg of baclofen (Wilson et al., 2011) impairs the ability

to discriminate between two concentrations of sucrose. Further, systemic baclofen at a

concentration of 3 mg/kg is capable of inducing conditioned taste aversion. However, there are no

data available to determine the effect of GABAB receptor ligands on conditioned taste aversion as

29
described above. The data from the transgenic animals suggest that presynaptic GABAB receptors

are necessary for this aversive association to be acquired, and that potentially the interplay between

presynaptic and postsynaptic receptors are necessary in order to alter information regarding the

association. Based on these data, it is possible that altering GABAB receptor activity in wild-type

animals would also affect task performance. These data are summarized in Table 8.

6.8. Conditioned Place Preference (CPP)

CPP is generally used to examine the reinforcing properties of drugs. A two chamber

apparatus is used for this task, with each chamber being contextually distinct from the other. Each

chamber is randomly assigned as the control chamber (where the animal is placed after saline

injections) or the experimental chamber (where the animal is placed after drug injections). Animals

spend time in each chamber for a given amount of time over several days to weeks after receiving

injections of either saline or a drug. After these pairings, the animal’s preference is tested by

allowing free access to both chambers. If a drug has reinforcing properties, the animal will spend

more time in the chamber associated with the drug. Conversely, if the drug has aversive properties,

the animal will spend more time in the saline-associated chamber. Numerous brain regions are

involved in CPP including the prefrontal cortex, nucleus accumbens, hippocampus, amygdala, and

the pedunculopontine tegmental nucleus (for substantial review, see Tzschentke, 2007). As

summarized in Table 9, GABAB1a-/- mice exhibit hyperlocomotion in response to cocaine

treatment; while GABAB1b-/- mice exhibit hyperlocomotion prior to drug exposure, they do not

differ from wildtype mice when exposed to cocaine (Jacobson et al., 2016). Further, GABAB1b-/-

mice appear to be insensitive to cocaine sensitization, as demonstrated by a lack of increased

locomotion in response to chronic cocaine treatment. While none of the mice (including wild-

30
types) in this study developed CPP, these data do suggest differential roles of the GABAB1 receptor

isoforms in the physiological responses to cocaine.

GABAB receptor PAMs (Voigt et al., 2011b; 2014) and agonists (Heinrichs et al., 2010;

Voigt et al., 2011a; Zarrindast et al., 2006b) help to alter the CPP of several addictive drugs,

including methamphetamine and morphine, regardless of systemic or intrahippocampal

administration. Further, these studies demonstrate the ability of these ligands to prevent the

acquisition (Zarrindast et al., 2006a), and recall (Zarrindast et al., 2006a) of CPP, as well as induce

the extinction of the CPP (Heinrichs et al., 2010; Voigt et al., 2014; 2011b; 2011a). What is more,

intrahippocampal administration of phaclofen significantly enhances CPP of morphine (Zarrindast

et al., 2006b). The ability for GABAB receptor PAMs or agonists to help extinguish this type of

learning, but not conditioned fear or conditioned taste aversion, may be related to neural regions

recruited for each task. For example, animals will self-administer baclofen into the median and

dorsal raphe nuclei, indicating reinforcing properties of the drug (Shin and Ikemoto, 2010).

Animals will also exhibit CPP to baclofen when it is infused into these regions (Shin and Ikemoto,

2010). However, when administered systemically, baclofen induces conditioned taste aversion,

which should not happen if the drug were reinforcing (Wilson et al., 2011). Possibly, systemic

administration of baclofen produces aversive side effects, which might negate any reinforcing

properties of addictive drugs when administered together. Systemically activating the GABAB

receptor system appears to be an effective treatment for dissociating the reinforcing properties of

drugs of abuse.

31
6.9. Novel Object Recognition and Location

Novel object recognition (NOR) and novel object location (NOL) tests an animal’s ability

to discriminate between familiarity and novelty. During the acquisition phase, an animal is

presented with two objects that are identical and the time spent investigating the objects is

recorded. During the test phase, animals are presented with one of the objects during the

acquisition phase and new, unfamiliar object for NOR. In NOL, both of the original objects are

presented in the test phase, however one object has been relocated. In each phase of testing, time

spent investigating the objects is recorded. In order to test short-term memory, animals can be

tested the same day. If the animal remembers an object, it will not spend as much time investigating

the familiar object in NOR; in NOL, the animal should spend less time investigating the object

that has not moved. Long-term memory is usually tested 24 hours after the acquisition phase. An

animal spending equal amounts of time investigating the familiar and novel objects, or the objects

in the familiar and novel locations, marks impairment. Typically, rodents will investigate novelty

longer than familiarity.

These tasks are largely hippocampally-based (Antunes and Moita, 2010; I. Lee et al.,

2005), and require the prefrontal cortex for consolidation (Akirav and Maroun, 2006). Deletion of

presynaptic GABAB receptors is detrimental for both NOR (Cullen et al., 2014; Jacobson et al.,

2007; Vigot et al., 2006) and NOL (Cullen et al., 2014) task performance (see Table 10). However,

the effect of postsynaptic GABAB receptors remains unclear. In one study, GABAB1b-/- mice were

impaired (Jacobson et al., 2007) in NOR, but another study found no effect of this genotype on

task performance (Vigot et al., 2006). Further, RGS7-/- mice are impaired in this task (Ostrovskaya

et al., 2014), but mice with enhanced postsynaptic GABAB receptor stability are not (Terunuma et

al., 2014). Since it is proposed that the RGS7-/- mice have decreased interaction between GABAB

32
receptors and GIRK channels, these mice likely experience decreased postsynaptic GABAB

receptor signaling. Thus, NOR may be more sensitive to decreased, but not increased, postsynaptic

GABAB signaling. Terunuma et al. (2014) found that the mice with enhanced postsynaptic GABAB

receptor signaling were impaired in NOL, which suggests that NOL may be a more sensitive task

for this increased signaling than NOR.

Higher concentrations (4 -25 mg/kg) of systemic baclofen disrupt both acquisition (C.-J.

Li et al., 2014; Pitsikas et al., 2003) and consolidation (Pitsikas et al., 2003) of NOR. Surprisingly,

intra-CA1 infusion of baclofen does not affect consolidation (Khanegheini et al., 2015), nor does

low concentrations (0.5 mg/kg) of systemic baclofen (Car and Wiśniewski, 1998). Systemic

administration of GABAB receptor antagonists does not appear to affect acquisition

(Kleschevnikov et al., 2012a) or consolidation (Pitsikas et al., 2003) of NOR. However, intra-CA1

infusions of phaclofen does impair NOR consolidation (Khanegheini et al., 2015). Far fewer

studies have investigated the effect of GABAB receptor ligands on NOL performance, however

they do seem to mimic the data form the transgenic animals. For instance, while baclofen infused

into the CA1 did not affect NOR performance, it does impair NOL performance (Khanegheini et

al., 2015). Systemic administration of CGP 55845 does not affect NOL acquisition (Kleschevnikov

et al., 2012a), but, surprisingly, Khanegheini et al. (2015) found that intra-CA1 infusion of

phaclofen impairs NOL consolidation. Although it is expected that a GABAB receptor agonist and

antagonist would have opposite behavioral effects, it is possible that baclofen and phaclofen are

affecting presynaptic and postsynaptic GABAB receptors differentially. Alternatively, it may be

that NOL is simply sensitive to altered hippocampal GABAB receptor activity, regardless of

whether that activity is increased or decreased.

33
 These data suggest that presynaptic GABAB receptors are necessary for both NOR and

NOL acquisition, but that NOL may be more sensitive to altered GABAB receptor activity.

However, this conclusion would be stronger if GABAB1b knockout and other transgenic mice were

also tested in NOL. Further, a better conclusion could be drawn if any ligand improved

performance in this task; however, as stated above, these tasks simply may be sensitive to altered

hippocampal function.

6.10. Barnes Maze

The Barnes maze is a spatial navigation task. Typically, the apparatus is a round, elevated

platform with escape holes along the diameter. One of the escape holes opens into a dark escape

box, which rodents find rewarding, whereas the remaining holes simply open to the floor or are

covered from the under-side of the platform with a plexiglass cover. Animals are released in the

center of the platform and must utilize extra-maze spatial cues to navigate to the dark escape box.

Performance in this task is measured by the latency to escape, as well as with a probe trial similar

to the MWM. Also similar to the MWM, this task requires proper hippocampal function in order

to be solved (Deacon and Rawlins, 2002; Paylor et al., 2001).

Transgenic mice expressing more stable postsynaptic GABAB receptors exhibit impaired

performance in this task (see Table 11; Terunuma et al., 2014). Systemic administration of

baclofen impairs recall of this task, but does not affect acquisition (X. Li et al., 2013). However,

systemic administration of BHF 177 impairs acquisition, but not recall (X. Li et al., 2013). Because

there are so few studies to review, it is difficult to draw conclusions; however, it is possible that

these ligands may affect postsynaptic GABAB receptors differently.

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6.11. Conditional Space Color Task

This task required Rhesus monkeys to learn the location of a food reward based on the

color and location of beakers. For example, a yellow beaker only contained a reward if it was

situated on the left in a choice of three cups; a blue beaker only had a reward if it was found on the

right; and a red beaker only had a reward if it was on the left. The animals were trained with trials

of increasing difficulty, and with a total of three conditions (yellow, blue, red; brown, green,

orange; cross, circle, stripes), with training in between each condition. Presumably, this task

requires the hippocampus and prefrontal cortex. The administration of CGP 36742 improved

performance across the conditions, as compared to placebo treatment (see Table 11; Mondadori et

al., 1993). Although this study is unique and did not examine the effect of an agonist, these data

suggest that blockade of the GABAB receptors has the potential to improve learning and memory

involving complex rules.

6.12. Social Recognition

Similar to object recognition, social recognition tasks require an animal to demonstrate

recognition of a familiar animal by spending less time investigating it. When presented with

familiar and novel partners, the animal being tested ought to spend more time investigating and

interacting with the novel partner. Improved performance in this task is marked by more time spent

investigating the novel versus familiar partner. This task is thought to involve the ventral

striatopallidal system and the amygdala (Young, 2002), as well as the hippocampus (Kogan et al.,

2000; Uekita and Okanoya, 2011). Systemic treatment with CGP 36742 prior to the presentation

of the familiar and novel partners produces improves performance in this task (see Table 11;

35
Mondadori et al., 1993; 1996a). These data suggest that the reduction of GABAB receptor activity

facilitates recall of social memory.

6.13. General Behavioral Conclusions

For some of the above behavioral tasks, it is difficult to draw a conclusion about the effect

of altered GABAB receptor activity for a variety of reasons. In some cases, only one type of ligand

is utilized. In others, the same ligand or transgenic mutation differentially affects behavior in

different studies. Some of the apparent disagreements may simply stem from strain or sex

differences (de Velasco et al., 2015), or from the effects of different concentrations and different

timing of administration of a particular ligand. While it is understood that research generally takes

a tortuous path to its conclusions, the impact of altered GABAB receptor function on learning and

memory in intact animals may benefit from studies that are more complementary to those that are

already published. For some behavioral paradigms, studies that replicate protocols previously

utilized will enable a better comparison of the results. As more sophisticated techniques become

available, like optogenetics, more precise examinations of the role of GABAB receptor function

can be conducted. Traditional knockout studies provide limited data because of the lack of normal

neuronal function during development. Further, better pharmacological examinations can be

conducted to examine the impact of presynaptic versus postsynaptic receptor function on learning

and memory. Similarly, as the GABAB receptor and its effectors becomes better understood, it

may become apparent that certain ligands differentially affect receptor responses (Rajalu et al.,

2015). Overall, however, the data indicate that proper GABAB receptor function is a necessary

component to a variety of learning and memory paradigms.

36
7. Changes to GABAergic and GABAB-related Markers Within Clinical Populations

Learning and memory deficits are hallmarks of several diseases and psychological

disorders. While these deficits likely stem from a number of pathways, many of these populations

demonstrate changes to GABAB-related markers, indicating that changes to this system may be

detrimental. This section reviews these changes within human populations, in addition to

predictions made by animal models of those same diseases and disorders.

7.1. Schizophrenia

Examinations of postmortem brain tissue from patients with schizophrenia reveal

decreased expression of GABAB receptors and subunits compared to control tissue throughout

several regions. GABAB receptor density is decreased within the inferior temporal cortex,

entorhinal cortex, dentate gyrus, CA1, CA2, CA3, and CA4 (Mizukami et al., 2002; 2000). Subunit

specific changes are also present. For instance, the prefrontal cortex has decreased levels of the

GABAB1a receptor isoform (Ishikawa et al., 2005), and the cerebellum has decreased amounts of

both GABAB1 and GABAB2 receptor subunits (Fatemi et al., 2011).

Patients with schizophrenia also demonstrate GABAergic alterations. For instance, patients

with schizophrenia have decreased parvalbumin and GAD67 expression in GABAergic

interneurons (Cherlyn et al., 2010; Gonzalez-Burgos et al., 2010; Guidotti et al., 2005; Torrey et

al., 2005; Zhao et al., 2007), as well as deficits in frontal cortex chandelier neurons that give rise

to oscillatory gamma activity (Kantrowitz et al., 2009). Further changes are apparent in other

GABAergic markers like GABAA receptors (Cherlyn et al., 2010; C. Deng and X.-F. Huang, 2006;

Gonzalez-Burgos et al., 2010; Zhao et al., 2007), GABA concentration (Öngür et al., 2010),

reuptake sites (Wassef et al., 2003), and GABA currents (Benes, 2010). Together, these results

37
indicate widespread changes to the GABAB receptor and GABAergic functioning within this

population. These differences may be indicative of decreased inhibition within the affected

regions.

Liu and colleagues (2009) examined the effect of transcranial magnetic stimulation (TMS)

of the primary motor cortex on cortical inhibition in controls, medicated, and unmedicated patients

with schizophrenia. The long-interval cortical silent period (CSP) is an indication of GABAB

receptor function (Premoli et al., 2014). The GABAB-mediated CSP was enhanced in medicated

patient and was inversely correlated with negative symptoms. These data suggest that GABAB

receptor dysfunction could underlie the pathophysiology of these symptoms. Additional

differences were evident in the GABAA-mediated short-interval CSP, which were weakly

correlated with positive symptoms. The authors suggest that the altered inhibitory GABAergic

currents could differentially regulate symptoms of schizophrenia.

Another study examined the effect of TMS of the primary motor cortex on CSPs between

patients at-risk for schizophrenia, first-episode schizophrenia patients and controls (Hasan et al.,

2012b). At-risk and first-episode patients demonstrated reductions in the GABAA-mediated CSP.

Compared to both controls and at-risk patients, first-episode patients also exhibited an increase in

the GABAB-mediated CSP. Further, a similar study found prolonged CSPs and impaired LTD-like

plasticity in medicated patients compared to controls (Hasan et al., 2012a). Antipsychotic naïve

patients also exhibit deficits in the GABAA-mediated CSP, which were negatively correlated with

social cognition (Mehta et al., 2014). Further, evidence suggests that presynaptic GABAB receptors

may inhibit GABAA-mediated CSPs, whereas postsynaptic GABAB receptors may inhibit the

TMS-induced motor-evoked potentials (J. Chu et al., 2008). These data suggest that early disease

symptomology may be related to GABAA-mediated or presynaptic GABAB-mediated dysfunction,

38
whereas disease progression may be more affected by altered postsynaptic GABAB receptor

functioning.

While the above experiments examined the CSPs only within the primary motor cortex,

disturbances to cortical function are also found within the frontal cortex. For instance, patients

with schizophrenia exhibit altered gamma activity compared to controls while performing working

memory tasks (Barr et al., 2010; Basar-Eroglu et al., 2007; Chen et al., 2014; Cho et al., 2006).

Gamma activity within the frontal cortex (Chen et al., 2014) and working memory (Rogasch et al.,

2014) are related to GABA activity, and deficits may be ameliorated with GABAergic drugs (D.

A. Lewis et al., 2008).

Animal models of schizophrenia have demonstrated that GABAB receptor activity can alter

dopamine hyperactivity (Balla et al., 2009; Javitt et al., 2005) and alter glutamatergic activity

(Roenker et al., 2012), which are both suspected to contribute to symptoms of schizophrenia.

Additionally, patients with schizophrenia often exhibit impaired sensorimotor gating. Recent data

indicate that altering GABAB receptor function in early life is associated with sensorimotor deficits

later in adulthood (Bolton et al., 2015), suggesting these deficits seen in humans may arise from

neural changes in early life. In animal models, sensorimotor deficits are rescued by GABAB

receptor activation (Arai et al., 2008; Bortolato et al., 2004; 2007; Fejgin et al., 2009; Frau et al.,

2014), and enhanced with GABAB receptor blockade (Ma and Leung, 2011). An experimental

drug that promotes neurite growth was found to rescue sensorimotor gating deficits; the authors

suggest this effect was due to reversing the loss of GABAergic neurons typically seen in the animal

model used (Uehara et al., 2012). Baclofen also improves behavioral deficits suggested to arise

from disrupted excitatory-inhibitory signaling induced by altered glutamatergic activity, as well as

restores the disrupted excitatory-inhibitory signaling (Gandal et al., 2012). Further, GABAB

39
receptor PAMs were recently shown to alleviate behaviors associated with negative and cognitive

symptoms of schizophrenia (Wieronska et al., 2015). These data strongly implicate the GABAB

receptor as a potential target in the treatment of schizophrenia.

7.2. Epilepsy

Epilepsy is thought to stem from insufficient inhibitory tone (Meldrum, 1975), excessive

excitation (Meisler, 2005), or the imbalance between the two systems (DiNuzzo et al., 2014;

During and Spencer, 1993). Several GABAA receptor genes are implicated in childhood absence

epilepsy (Robinson et al., 2002). Patients with temporal lobe epilepsy (TLE) exhibit altered mRNA

expression of the GABAB receptor subunits in several hippocampal subregions compared to

control tissue (Billinton et al., 2001; Furtinger et al., 2003; Princivalle et al., 2003a). Altered

GABAB receptor density (Muñoz et al., 2002) and loss of interneurons (de Lanerolle et al., 1989)

within the hippocampus are also evident. Further, TLE patients often experience amnesia; the

hallmarks of this particular amnesia have also been reported in a patient receiving long-term

cerebral spinal fluid infusions of baclofen (Zeman et al., 2016).

Postmortem tissue from TLE patients that do not respond to treatment indicates more

severe GABAB receptor dysfunction. This dysfunction is characterized by smaller GABAB-

mediated IPSPs and altered paired-pulse depression activity compared to controls, possibly due to

decreased densities of pre- and postsynaptic GABAB receptors (Teichgräber et al., 2009). This

population also demonstrates decreased GABAB receptor functionality within the lateral amygdala

(Hüttmann et al., 2006). Further, tissue processed from gangliogliomas and surrounding areas

removed from epileptic patients indicate changes to both the GABAB and GABAA receptor systems

(Aronica et al., 2007). Taken together, these data indicate marked changes to and decreased

40
functionality of GABA receptors within the brain, which could underlie the propagation of seizure

activity.

Numerous animal models have been developed to examine epilepsy. These models

typically demonstrate changes that center around altered GABAergic signaling similar to the

clinical population. For instance, several models demonstrate a decrease in GABAB receptor

markers within the hippocampus immediately after induction of TLE; however, after time, these

markers tend to normalize or become upregulated (Furtinger et al., 2003; Straessle et al., 2003). A

genetic model of TLE exhibits decreased GABA uptake within the hippocampus (Janjua et al.,

1991), which could explain increased autoinhibition (Dugladze et al., 2013; Gloveli et al., 2003).

The implantation of inhibitory neurons into the hippocampus of a mouse model of TLE results in

a reduction of seizures and rescues behavioral deficits (Hunt et al., 2013). Further,

hyperexcitability may be treated with GABAB receptor PAMs (Lang et al., 2014). Other studies

have demonstrated that GABAB receptor antagonism can prevent TLE-associated amnesia

(Genkova-Papazova et al., 2000) and reverse LTP deficits (Leung and C. Wu, 2003).

Animal models of typical absence epilepsy (AE) exhibit altered expression of GABAB

receptors within the neocortex and corticothalamic circuit (Inaba et al., 2009; Lin et al., 1993;

Merlo et al., 2007; Princivalle et al., 2003b). Treatment with GABAB receptor agonists increases

spike-wave discharges (Bortolato et al., 2010), which can be decreased via GABAB receptor

antagonism (Bortolato et al., 2010; Kamiński et al., 2001). Further, GABAB receptor antagonism

can help improve memory retention (Getova and Bowery, 2001). Recent evidence also implicates

dysfunctional astrocytic GABA transport in typical AE (Pirttimaki et al., 2013).

Animal models of atypical AE exhibit increased markers of GABAB receptors (Snead et

al., 2000). Confirming this observation, over-expression of the GABAB1 receptor subunit produces

41
an atypical AE phenotype (Stewart et al., 2009; Y. Wu et al., 2007). Further, GABAB receptor

antagonism can block seizures, restore LTP deficits, and reverse cognitive impairments in this

model (Chan et al., 2006). Another type of epilepsy, infantile spasms (IS), appears to require the

GIRK channel (Blichowski et al., 2015). Typically, IS can be generated with high concentrations

of GABAB receptor agonists, however agonist treatment in mice lacking the GIRK2 subunit fails

to induce IS.

Because there are several distinct types of epilepsy, each with its own collection of

symptoms and effects on the brain, it is difficult to unravel the specific contribution of altered

GABAB receptor activity. However, it is clear that there is a distinct effect on and effect of GABAB

receptor activity within these clinical populations. Further, GABAB receptors appear to regulate

homeostatic firing within the hippocampus, and decreased hippocampal GABAB receptors may

underlie the generation of some seizure activity (Vertkin et al., 2015). Based on the data above,

however, it is clear that certain symptoms associated with epilepsy may be treated with GABAB

receptor ligands.

7.3. Alzheimer’s Disease (AD)

Postmortem hippocampal tissue of AD patients is characterized by increases of GABAB1

receptor proteins in the CA4 and CA3/2 subfields (Iwakiri et al., 2005). These increases are

correlated with the progression of neurofibrillary tangle pathology (Iwakiri et al., 2005). Fewer

GABAB receptors are found in subregions of the dentate gyrus, CA1 (D. C. M. Chu et al., 1987a),

and the superior frontal gyrus (D. C. M. Chu et al., 1987b). Further, the CA1 specifically exhibits

a decrease in the GABAB1 receptor subunit compared to control tissue (Iwakiri et al., 2005).

42
 A non-coding RNA discovered to produce an alternative splicing of the GABAB receptor

is upregulated in the frontal and temporal cortices of patients with AD (Massone et al., 2011). This

alternative splicing is triggered by inflammatory stimuli and results in altered GABAB-mediated

signaling, increases amyloid-β (Aβ) secretion, and increases the Aβ42/40 ratio. In a study utilizing

TMS, AD patients demonstrate an increase in the GABAB-mediated CSP, which was inversely

related to scores on a measure of neurological ability (Khedr et al., 2011).

Patients with AD exhibit alterations to other GABAergic markers, as well. GABA is

decreased in the temporal lobe, parietal lobe, occipital lobe, and cerebellum (Bai et al., 2014; Seidl

et al., 2001). Decreased amounts of GABAA receptors and GABAergic neurons are observed in

the hippocampus (D. C. M. Chu et al., 1987a; Inaguma et al., 1992). The enzymes responsible for

synthesizing and breaking down GABA are decreased within the cerebellum and hippocampus

(Burbaeva et al., 2014; Schwab et al., 2013). Recent evidence also implicates altered glial function

in AD. Postmortem tissue exhibits increased concentrations of GABA within astrocytes in the

hippocampus and temporal cortex (Jo et al., 2014; Z. Wu et al., 2014). Hippocampal astrocytes

also express increased amounts of GAD67 and the astrocytic GABA transporter (Z. Wu et al.,

2014). Similar to these postmortem findings, animal models of AD also display changes to glial

function. For instance, hippocampal reactive astrocytes exhibit high GABA content (Jo et al.,

2014; Z. Wu et al., 2014), which contributes to increased tonic GABA inhibition, impaired LTP,

and learning and memory deficits. Decreasing GABA rescues these deficits. Further, astrocytic

GABA may even target GABA receptors differently. In an AD model, astrocytes activated

GABAA receptors within the perforant pathway, producing inhibition; in wild-type animals,

however, this astrocytic GABA activated GABAB receptors, disinhibiting the perforant pathway

(Yarishkin et al., 2015).

43
 Aβ produces changes to inhibitory signaling similar to the changes observed when

GABAB-GIRK signaling is altered (Nava-Mesa et al., 2013). Recent data demonstrate that Aβ

decreases the expression of GIRK channel subunits (Mayordomo-Cava et al., 2015) and that Aβ

proteins associate with GABAB receptors (Schwenk et al., 2015). Additionally, intrahippocampal

injections of Aβ decreases the number of neurons expressing GABAergic markers (Villette et al.,

2012). Transgenic mice expressing Aβ exhibit impaired neurogenesis and excitatory-inhibitory

imbalance in the hippocampus, which is normalized when GABAergic signaling is blocked (Sun

et al., 2009). In transgenic mice expressing apolipoprotein E4 and tau, administration of a GABAA

receptor agonist rescues learning and memory deficits (Andrews-Zwilling et al., 2010). When tau

is removed from this transgenic strain, GABAergic neuron loss and learning and memory deficits

are reversed. However, the administration of a GABAA receptor antagonist eliminates the

beneficial effects of the lack of tau. These data suggest that traditional markers of AD may interact

with and affect GABAergic signaling.

Patients with Down syndrome exhibit AD-like neurodegeneration. While postmortem

investigations do not necessarily indicate the same changes to GABAergic markers as AD patients

(Seidl et al., 2001), animal models do suggest altered GABAergic signaling contributes to the

disorder. Transgenic animals exhibit several upregulated GABAergic markers within the

hippocampus (Hernández-González et al., 2014), and learning and memory deficits are mediated

by the dentate gyrus (Smith et al., 2013). Normalizing GABA release rescues hippocampal-

dependent learning and memory deficits (Begenisic et al., 2013). Animal models exhibit increased

GABAB-mediated GIRK current and GIRK channel expression within the hippocampus (Best et

al., 2012; 2007; Kleschevnikov et al., 2012b), which are suggested to mediate cognitive deficits.

44
When administered a GABAB receptor antagonist, transgenic animals display normal learning and

memory behavior in several domains (Kleschevnikov et al., 2012a).

Interestingly, one of the more extensively studied GABAB antagonists, CGP 36742, had

progressed to Phase II trials to treat AD (Davies et al., 2005; Froestl et al., 2004). Compared to

placebo, it improved working memory and attention. However, it has since failed to progress to

Phase III testing (Sabbagh, 2009). These data indicate that some of the memory impairments seen

in AD patients could be the result of GABA dysfunction and altered GABAB receptor function.

Potential GABAergic therapeutics may target specific GABAB receptors, GIRK channels, or even

astrocytes.

7.4. Autism Spectrum Disorder (ASD)

Postmortem tissue from patients with ASD exhibits widespread changes to the GABA

system. Alterations include decreased amounts of GAD65, GAD67, GABAB1, GABAB2, and

several GABAA receptor subunits in the cerebellum, superior frontal and parietal lobes compared

to a control population (Fatemi et al., 2009; 2008; 2002; 2010). Postmortem tissue from patients

with ASD also has decreased GABAB and GABAA receptor density in the anterior and posterior

cingulate cortex and the fusiform gyrus (Oblak et al., 2011; 2010).

ASD patients exhibit sensorimotor gating deficits (which, as reviewed above, may be a

result of altered GABAB receptor function) and GABA-mediated alterations to EEG phase

resetting (Perry et al., 2007; Thatcher et al., 2009). Evidence suggests, however, that the changes

to the GABAA receptor may be more detrimental to ASD than those to GABAB receptors. For

instance, alterations to the GABAA system may underlie the comorbidity of ASD and epilepsy

(Kang and Barnes, 2012). Additionally, the GABAA-mediated CSP is related to early language

45
delay in patients with ASD (Enticott et al., 2013). Further, transgenic animals lacking one of the

GABAA receptor subunits exhibit behavioral deficits characteristic of ASD (DeLorey et al., 2008).

However, as discussed above, GABAB receptors can regulate GABAA receptor activity;

thus, it is possible these changes to GABAA receptor activity could be moderated by GABAB

receptor dysfunction. Further, baclofen alleviates ASD symptoms in an animal model (Silverman

et al., 2015). Baclofen also reverses synaptic abnormalities in an animal model of Fragile X

syndrome (Henderson et al., 2012). Additionally, dysregulated feed-forward inhibition in a model

of Fragile X syndrome is reversed by presynaptic GABAB receptor activation, or by blocking both

presynaptic and postsynaptic GABAB receptors (Wahlstrom-Helgren and Klyachko, 2015).

While there may be more apparent disruption to GABAA receptor functionality, it is

possible that these changes are driven by GABAB receptor dysfunction. In either case, there is

evidence for altered GABAergic signaling throughout the brain in ASD. Possibly, some of the

symptoms of ASD may be managed with GABAB receptor ligand treatment.

7.5. Mood Disorders

Patients with major depressive disorder (MDD) and bipolar disorder (BPD) exhibit

decreased levels of GABAB1 and GABAB2 receptor subunits in cerebellar and prefrontal cortical

tissue as compared to controls (Fatemi et al., 2011; Ishikawa et al., 2005). Changes to KCTD

auxiliary subunits are also present in these clinical populations (M. T. M. Lee et al., 2011; Sibille

et al., 2009). Additionally, patients with MDD and BPD exhibit decreased mRNA and expression

of GAD65 and GAD67 in the cerebellum, prefrontal cortex, and hippocampus (Fatemi et al., 2005;

Heckers et al., 2002; Torrey et al., 2005). While free GABA present in cerebral spinal fluid is

decreased in patients with MDD (J. J. Mann et al., 2014), magnetic resonance scanning reveals

46
increased GABA in several regions in BPD patients (Brady et al., 2013). Patients with any history

of MDD exhibit deficits in the GABAB-mediated CSP, but those patients with treatment resistant

MDD also exhibit GABAA-mediated CSP deficits (Levinson et al., 2010).

Animal models of mood disorders exhibit altered GABAB receptor signaling (Mokrushin

et al., 2009), and GABAB receptor ligands help to ameliorate depression-like symptoms

(Frankowska et al., 2007; Slattery and Cryan, 2006). Transgenic animals lacking the KCTD12

auxiliary subunit exhibit increased fear learning similar to what is observed in MDD (Cathomas et

al., 2015). Further, rapid antidepressants appear to require GABAB receptors (Workman et al.,

2013). In order to be effective, rapid antidepressants may recruit and alter GABAB receptor

signaling (Workman et al., 2015). When tested in a clinical population, ketamine increased both

GABA and glutamate levels in the medial prefrontal cortex (Milak et al., 2015). Together, these

data strongly implicate an altered GABAergic system in mood disorders.

7.6. Addiction

Few studies have examined changes to GABAB receptors within this population. Compared

to the GABAB receptor, alterations to GABAA receptor markers throughout the brain are well

documented (Bhandage et al., 2014; Kreek et al., 2004; Laukkanen et al., 2013). However, one

study found decreases to the GABAB1 receptor subunit, GABAA receptor markers, and GAD65/67

mRNA in postmortem hippocampal tissue from alcoholics and cocaine addicts (Enoch et al.,

2012). These neurological changes, however, could result from drug effects, and may not represent

alterations that may make somebody susceptible to addiction. For example, decreased GABAB

receptor binding in several regions, including the nucleus accumbens, amygdala, and prefrontal

cortex, are associated with chronic cocaine administration (Frankowska et al., 2008a). Further,

47
reinstatement of cocaine-seeking behavior increases GABAB receptor binding in the nucleus

accumbens and prefrontal cortex (Frankowska et al., 2008b). In addition to neural changes, genetic

variants related to addiction have been identified. One study found a GABAB2 receptor allelic

variation associated with nicotine dependence (Beuten et al., 2005). Another study, however, failed

to find such an association, instead finding several GABAA receptor polymorphisms (Agrawal et

al., 2008).

In addition to affecting CPP (see above), GABAB receptor ligands can affect other

behaviors related to addiction and drugs of abuse (Frankowska et al., 2010). For instance, baclofen

can block the effects of chronic stress on morphine-induced CPP (Meng et al., 2013). Baclofen

and GS 39783 block sensitivity and decrease drug-induced hyperactivity related to cocaine and

morphine (Bartoletti et al., 2007; Lhuillier et al., 2006; Steketee and Beyer, 2005). Baclofen also

prevents reinstated drug-seeking behavior (Spano et al., 2007), and reduces cocaine-induced

reward enhancement (Dobrovitsky et al., 2002).

Systemic baclofen reduces nicotine-induced antinociception, but saclofen decreases both

nicotine-induced hypolocomotion and antinociception (Varani et al., 2014). Possibly, locomotion

and nociception utilize different pathways that are differentially affected by GABAB receptor

ligands. Further, in GABAB1-/- mice treated with nicotine, the effects of nicotine withdrawal are

prevented (Varani et al., 2015). These data suggest that functional GABAB receptors are required

for either the acquisition of nicotine addiction or for the expression of nicotine withdrawal.

Alcohol intake and withdrawal is also altered with GABAB receptor ligands. Baclofen and

BHF 177 decrease alcohol self-administration in rodents (Colombo et al., 2003; Orrù et al., 2012).

Further evidence implicates an interaction between the GABAB receptor system and

endocannabinoids in alcohol intake (Méndez-Díaz et al., 2013). Other PAMs are also effective at

48
decreasing alcohol intake (Filip et al., 2014). Further, baclofen is effective in the clinical

population at decreasing alcohol intake and withdrawal symptoms (Addolorato et al., 2006;

Colombo et al., 2000; J. Liu and Wang, 2015).

Interestingly, however, when administered baclofen, human subjects exhibit enhanced

reinforcement learning (Ort et al., 2014), and the GABAergic pathway is essential for reward

processing through the hippocampus (Vega-Flores et al., 2014). Drugs of abuse can alter GABAB

receptor activity. Cocaine administration decreases GABAB-GIRK signaling and GIRK channels

ultimately downregulate, suggesting decreased inhibitory signaling as a mechanism of action

(Arora et al., 2011). Possibly, GABAB receptor ligands help to restore homeostatic activity in these

pathways that are affected by drugs of abuse.

7.7. General Conclusions Regarding Clinical Populations

While each clinical population exhibits its own set of deficits and alterations to GABAergic

markers, the evidence suggests that the GABAB receptor system is affected in each of them.

However, it is difficult to parse out the effects of the disease or disorder on GABAB receptor

function versus the effects of altered GABAB receptor function on the etiology of these

neuropsychological disorders. Data from the behavioral studies indicate that GABAB receptor

ligands may be able to rescue some of the deficits seen within a particular clinical population.

Indeed, GABAB ligands are currently being used to treat certain populations. As the receptors and

the ligands become better understood, the GABAB receptor may become a therapeutic target for

more patients in the future.

49
8. Concluding Remarks

Although we are far from understanding the full contribution of altered GABAergic

signaling to these behaviors, diseases, and disorders, it is possible that some of the differences

observed in the behavioral outcomes and across populations may be due to distinct populations of

these receptors. Pre- and postsynaptic GABAB receptors in the CA1 (Dutar and Nicoll, 1988) and

the somatosensory cortex (Deisz et al., 1993) in rats demonstrate different pharmacological

properties. The function of the GABAB1 receptor isoforms may be different, as well (Kasten and

Boehm, 2015). For instance, mice lacking the GABAB1a receptor isoform exhibit impaired

glutamate release, whereas glutamate release in GABAB1b-/- mice is intact (Waldmeier et al., 2008).

Furthermore, different regions of the brain respond differently to the same GABAB receptor

ligands (Hensler et al., 2011). Possibly, some of these response differences may be related to the

KCTD auxiliary subunits associated with a given GABAB receptor (Rajalu et al., 2015).

Cell type and target of GABAergic neurons can also influence the property of these cells.

For instance, GABAergic interneurons and pyramidal cells of the stratum radiatum of the

hippocampus exhibit different capacities for activity-dependent plasticity (Patenaude et al., 2005),

and perisomatic-targeting cells respond differently to GABA compared to dendritic-targeting cells

(Booker et al., 2013). These population differences could be due to other GABAB1 receptor

subtypes (Tiao et al., 2008). More specific drugs that target a particular subunit potentially could

affect behavior differentially. Additionally, the discovery of specific deficits related to GABAB

receptor function or specific GABAB receptor subtypes or populations in the reviewed populations

could lead to better pharmaceutical treatments.

Though perhaps the mechanisms are not fully understood, it is exceedingly evident that

proper GABAB receptor function is important for many factors that influence learning and

50
memory. Additionally, several disorders are sensitive to alterations to the GABAB receptor system,

and changes to this system could underlie their etiology. Through more research, compounds based

on altering the function of a specific type of GABAB receptor (either based on brain region or

synaptic location) may help restore cognition for patients of certain diseases and psychological

disorders.

51
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Figures captions

Figure 1. Presynaptic mechanisms of the GABAB receptor. When activated, the presynaptic
GABAB receptor acts to inhibit adenylyl cyclase (AC) and the cyclic AMP (cAMP) pathway. One
of the actions of the AC signaling pathway is to recruit vesicles full of neurotransmitter (NT) to
the cell membrane. Voltage-gated calcium channel (VGCC) activity is also inhibited by
presynaptic GABAB receptors. Inhibition of VGCCs also leads to less NT release.

Figure 2. Postsynaptic mechanisms of the GABAB receptor. Activated postsynaptic GABAB

receptors inhibit adenylyl cyclase (AC), which inhibits the cyclic AMP (cAMP) cascade. One of
the downstream targets of AC and cAMP is CREB, which initiates transcription in the nucleus
(Nuc). The beta-gamma subunit of the GABAB receptor, however, can interact directly with CREB
to initiate transcription. Voltage-gated calcium channels (VGCC) are also inhibited by the beta-
gamma subunit, which leads to less depolarization of the postsynaptic neuron. Activated
postsynaptic GABAB receptors also activate inwardly-rectifying potassium channels (GIRK) to
induce hyperpolarization.

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Fig1

84
Fig 2

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Table 1 GABAB Receptor Ligands
Ligand Classification Chemical name Reference
Baclofen Agonist (R)-4-Amino-3-(4-chlorophenyl)butanoic Falch et al.
acid (1986)
BHF 177 Positive N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2- Guery et al.
allosteric methyl-5-[4-(trifluoromethyl)phenyl]-4- (2007)
modulator pyrimidinamine
CGP 35348 Antagonist (3- Froestl et al.
Aminopropyl)(diethoxymethyl)phosphinic (1995)
acid
CGP 36742 Antagonist P-(3-Aminopropyl)-P-butyl-phosphinic acid Froestl et al.
(1995)
CGP 44532 Agonist (3-amino-2(S)- Ong et al.
hydroxypropyl)methylphosphinic acid (2001)

CGP 46381 Antagonist (3- Froestl et al.

Aminopropyl)(cyclohexylmethyl)phosphinic (1995)
acid
CGP 55845 Antagonist (2S)-3-[[(1S)-1-(3,4- Bittiger et al.
Dichlorophenyl)ethyl]amino-2- (1993)
hydroxypropyl](phenylmethyl)phosphinic
acid hydrochloride
CGP 56433 Antagonist (3-(1-((3- Getova et al.
(Cyclohexylmethyl)hydroxyphosphinyl)-2- (1997)
hydroxypropyl)amino)ethyl)benzoic acid
CGP 61334 Antagonist [3-{{3-[(diethoxymethyl)hydroxy Getova et al.
phosphinyl]propyl] amino}methyl]-benzoic (1997)
acid
CGP 62349 Antagonist [3-[1-R-[[2-(S)-hydroxy-3-[hydroxy-[4- Froestl et al.
methoxy- phenyl]-methyl]-phosphinyl]]- (2007)
propyl]-aminoethyl]-benzoic acid
CGP 63360a Antagonist Cyclohexylmethyl-2-(S)-hydroxy-3-[(6-oxo- Getova and
1,6-dihydro-pyridin-3-ylmethyl)- amino]- Dimitrova
propyl-phosphinic acid, hydrochloride (2007)
CGP 71982 Antagonist 3-[6-(cyclohexylmethyl-hydroxy- Froestl et al.
phosphinyl-methyl)-morpholin-3-yl] (2007)
benzoic acid
CGP 76290a Antagonist 3-[(3R,6R)-6-(Cyclohexylmethyl-hydroxy- Froestl et al.
phosphinoylmethyl)-morpholin-3-yl]benzoic (2007)
acid


86
CGP 76291a Antagonist 3-[(3-S, 6S) -6-(Cyclohexylmethyl-hydroxy- Froestl et al.
phosphinoylnethyl)-morpholin-3-yl]benzoic (2007)
acid
CGP 7930 Positive 2,6-di-tert-butyl-4-(3-hydroxy-2,2- Urwyler et al.
allosteric dimethylpropyl)-phenol (2001)
modulator
Fendiline Positive N-[3,3-diphenylpropyl]-- Ong and Kerr
allosteric methylbenzylamine hydrochloride (2005)
modulator
GS 39783 Positive N,N'-dicyclopentyl-2-(methylthio)-5-nitro- Urwyler et al.
allosteric 4,6-pyrimidinediamine (2003)
modulator
Phaclofen Antagonist (RS)-3-Amino-2-(4- Kerr et al.
chlorophenyl)propylphosphonic acid (1987)

Saclofen Antagonist (RS)-3-Amino-2-(4- Bowery (1989)

chlorophenyl)propylsulfonic acid

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Table 2 Summary of the effect of GABAB ligands on passive avoidance
Ligand Route, time of Species
Effect Reference
(Concentration) administration (sex)
Baclofen (0.5) IP, post- Wistar (m)  Car and Wiśniewski (1998)
training
Baclofen (0.5) IP, 30 m pre- Wistar (m)  Car and Wiśniewski (1998)
test
Baclofen (0.25) IP, 30 m pre- Wistar (f)  Car and Wiśniewska (2006)
training
Baclofen (0.25) IP, post- Wistar (f)  Car and Wiśniewska (2006)
training
Baclofen (0.25) IP, 30 m pre- Wistar (f)  Car and Wiśniewska (2006)
test
Baclofen (0.25) IP, 30 m pre- Wistar (f)  Car and Michaluk (2012)
training
Baclofen (3, 10, IP, post- CD1 mice  Castellano et al. (1989)
30) training (m)
Baclofen (10) IP, 120 m CD1 mice  Castellano et al. (1989)
post-training (m)
Baclofen (0.01, Intra- Sprague-  Castellano et al. (1989)
0.1 nmol) amygdala, Dawley
post-training (m)
Baclofen (5, 10, IP, post- C57BL/6J  Castellano et al. (1993)
20) training mice (m)
Baclofen (5, 10, IP, post- DBA/2  Castellano et al. (1993)
20) training mice (m)
Baclofen (1, 3) SC, 30 m pre- CD1 mice  Cryan et al. (2004)
training (m)
Baclofen (1, 3) PO, 60 m pre- Sprague-  Cryan et al. (2004)
training Dawley
(m)
Baclofen (10) IP, 30 m pre- C57BL/6J  Dubrovina and Zinov'ev
training mice (m) (2008)
Baclofen (10) IP, post- Wistar (m)  Georgiev et al. (1988)
training
Baclofen (0.75) IP, 30 m pre- Wistar (m)  Kuziemka-Leska et al. (1999)
test
Baclofen (1, 2, IP, 30 m pre- Wistar (m)  Nakagawa et al. (1993)
4, 8) training

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Table 2 (continued)
Summary of the effect of GABAB ligands on passive avoidance
Ligand Route, time of Species
Effect Reference
(Concentration) administration (sex)
Baclofen (1, 2, IP, 30 m pre- Wistar (m)  Nakagawa et al. (1993)
4, 8) training/pre-
test
Baclofen (1, 2, IP, 30 m pre- Wistar (m)  Nakagawa et al. (1993)
4, 8) test
Baclofen (1, 5, SC, post- ICRC  Saha et al. (1993)
10) training Swiss
mice (m)
Baclofen (5, 10) IP, post- Fischer  Swartzwelder et al. (1987)
training 344 (m)
Baclofen (5, 10) IP, 10 m post- Fischer  Swartzwelder et al. (1987)
training 344 (m)
Baclofen (5, 10) IP, 60 m post- Fischer  Swartzwelder et al. (1987)
training 344 (m)
Baclofen IP, 30 m pre- NMRI  Zarrindast et al. (1998)
(0.125, 0.25, training Mice (m)
0.5, 1)
Baclofen (0.25, Intra-CA1, Wistar (m)  Zarrindast et al. (2002)
0.5, 1, 2 ug) post-training
Baclofen (1, IP, 30 m post- NMRI  Zarrindast et al. (2004a)
1.25, 1.5, 2, 4) training Mice (m)

Baclofen (0.25, ICV, post- Wistar (m)  Zarrindast et al. (2004b)

0.5, 1, 2 ug) training
Baclofen (0.5, Intra-CA1, 5 d NMRI  Zarrindast et al. (2008)
0.75, 1, 1.5, 2 pre-training Mice (m)
ug)
CGP 35348 IP, post- C57BL/6J  Castellano et al. (1993)
(100, 200, 300) training mice (m)
CGP 35348 IP, post- DBA/2  Castellano et al. (1993)
(100, 200, 300) training mice (m)
CGP 35348 (10, IP, post- ICRC  Saha et al. (1993)
50) training Swiss
mice (m)
CGP 35348 Intra-CA1, Wistar (m)  Zarrindast et al. (2002)
(2.5, 5, 10, 25, post-training
50 ug)

89
Table 2 (continued): Summary of the effect of GABAB ligands on passive avoidance
Ligand Route, time of Species
Effect Reference
(Concentration) administration (sex)
CGP 35348 ICV, post- Wistar (m)  Zarrindast et al. (2004b)
(2.5, 5, 10 ug) training
CGP 35348 Intra-CA1, 5 d NMRI  Zarrindast et al. (2008)
(2.5, 5, 10, 20, pre-training Mice (m)
40 ug)
CGP 36742 (3, IP, post- Wistar (m)  Genkova-Papazova et al.
30, 100) training (2000)
CGP 36742 PO, 60 m pre- MA 01  Mondadori et al. (1993)
(0.1, 0.3, 1, 3, training mice (m)
10, 30, 100)
CGP 36742 PO, post- MA 01  Mondadori et al. (1993)
(0.3, 3, 30) training mice (m)
CGP 36742 (10) IP, post- Tif MAGf  Mondadori et al. (1996b)
training SPF mice
(f)
CGP 36742 (50) IP, 14 d pre- Mice (m)  Yu et al. (1997)
training
CGP 63360a PO, 15 d pre- Wistar (m)  Getova and Dimitrova (2007)
(0.001, 0.01, training
0.1)
CGP 76290a PO, 15 d pre- Wistar (m)  Getova and Dimitrova (2007)
(0.01, 0.1) training
CGP 76291a PO, 15 d pre- Wistar (m)  Getova and Dimitrova (2007)
(0.01, 0.1) training
GS 39783 (1, 3, PO, 60 m pre- CD1 mice  Cryan et al. (2004)
10, 30, 100) training (m)

GS 39783 (25, PO, 60 m pre- Sprague-  Cryan et al. (2004)

50, 100) training Dawley
(m)
Phaclofen (5) IP, 30 m pre- C57BL/6J  Dubrovina and Zinov'ev
training mice (m) (2008)
Phaclofen (0.5, IP, 45 m pre- Mice (m)  Zarrindast et al. (1998)
1, 2, 4, 8) training
x x B1-/- (m/f)  Schuler et al. (2001)

90
Table 2 (continued): Summary of the effect of GABAB ligands on passive avoidance
Ligand Route, time of Species Effect Reference
(Concentration) administration (sex)
x x B1a-/- (m)  Jacobson et al. (2007)
x x B1b-/- (m)  Jacobson et al. (2007)
x x B2-/-  Gassmann et al. (2004)
Bold = Effective concentration; (m) = male; (f) = female;  = improved;  = impaired;  = Unchanged; Pre-
training = before acquisition, before trial not specifically a recall trial; Pre-test = before recall trial; Post-
training = after acquisition or trial not specifically a recall trial; ICV = intracerebroventricular; IP =
intraperitoneal; SC = subcutaneous; PO = per os/oral; m = minutes; d = days; ligand concentrations are in
mg/kg unless otherwise noted

Table 3 Summary of the effect of GABAB ligands on active avoidance

Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Baclofen (5, 10, Intra-rCC, post- CD1 mice (m)  Farr et al. (2000)
20, 40 ug) training
Baclofen (1.5 Intra-PPN, 17 h Sprague-Dawley  Fogel et al.
nmol) post-training (m) (2010)
Baclofen (2, 5, IP, post-training Wistar (m)  Georgiev et al.
10, 20) (1988)
Baclofen (0.75) IP, 30 m pre- Wistar (m)  Kuziemka-
training Leska et al.
(1999)
Baclofen (0.25, IP, 30 m pre-test LAKA mice  Sharma and
0.5) Kulkarni (1993)
Baclofen (2, 3, SC, 30 m pre-test Long-Evans (m)  Stuchlik and
3.5, 4, 6) Vales (2009)
CGP 35348 IP, 30 m pre-test LAKA mice  Sharma and
(100, 200) Kulkarni (1993)
CGP 36742 (3, IP, post-training Wistar (m)  Genkova-
30, 100) Papazova et al.
(2000)
CGP 36742 IP, pre- Wistar (m)  Getova et al.
(100) training/pre-test (1997)

91
 CGP 36742 (50) IP, 14 d pre- Mice (m)  Yu et al. (1997)
training
CGP 55845 IP, 30 m pre- Wistar (m)  Getova and
(0.01, 0.1, 1) training/pre-test Bowery (1998)
CGP 56433 (1) IP, pre- Wistar (m)  Getova et al.
training/pre-test (1997)
CGP 61334 (1) IP, pre- Wistar (m)  Getova et al.
training/pre-test (1997)
CGP 62349 IP, 30 m pre- Wistar (m)  Getova and
(0.01, 0.1, 1) training/pre-test Bowery (1998)
CGP 63360a PO, 15 d pre- Wistar (m)  Getova and
(0.001, 0.01, training Dimitrova
0.1) (2007)

Table 3 (continued) Summary of the effect of GABAB ligands on active avoidance

Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
CGP 71982 IP, 30 m pre- Wistar (m)  Getova and
(0.01, 0.1, 1) training/pre-test Bowery (1998)
CGP 76290a PO, 15 d pre- Wistar (m)  Getova and
(0.01, 0.1) training Dimitrova
(2007)
CGP 76291a PO, 15 d pre- Wistar (m)  Getova and
(0.01, 0.1) training Dimitrova
(2007)
Saclofen (0.25, Intra-rCC, post- CD1 mice (m)  Farr et al. (2000)
0.5, 1, 2.5, 5 ug) training
Bold = Effective concentration; (m) = male;  = improved;  = impaired;  = Unchanged; Pre-training =
before acquisition, before trial not specifically a recall trial; Pre-test = before recall trial; Post-training = after
acquisition or trial not specifically a recall trial; IP = intraperitoneal; SC = subcutaneous; PO = per os/oral; m =
minutes; d = days; h = hours; rCC = right cingulate cortex; PPN = pedunculopontine nucleus; ligand
concentrations are in mg/kg unless otherwise noted

92
Table 4 Summary of the effect of GABAB ligands on Morris water maze
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Baclofen (0.2, 2, Intra-dH, 60 m Wistar (m)  Arolfo et al.
20 mM) pre-training (1998)
Baclofen (0.25) IP, 30 m pre- Wistar (f)  Car and
training Michaluk (2012)
Baclofen (5 ug) Intra-EC, 15 m Sprague-Dawley  P.-Y. Deng et al.
pre-training (m) (2009)
Baclofen (12.5, IP, 19 h pre- Sprague-Dawley  C.-J. Li et al.
25) training (m) (2014)
Baclofen (1, 3, IP, 20 m pre- Long-Evans (m)  McNamara and
6) training/pre-test Skelton (1996)
Baclofen (1, 2, IP, 30 m pre- Wistar (m)  Nakagawa et al.
4) training (1995)
Baclofen (4) IP, 30 m pre- Wistar (m)  Nakagawa and
training Takashima
(1997)
CGP 35348 (2.5, Intra-CA1, 15 m Wistar (m)  Shahrzad and
5 ug) pre-training Nasser (2015)
CGP 35348 (2.5, Intra-CA1, post- Wistar (m)  Shahrzad and
5 ug) training Nasser (2015)
CGP 35348 (2.5, Intra-CA1, 15 m Wistar (m)  Shahrzad and
5) pre-test Nasser (2015)
CGP 36742 (3, PO, 90 m pre- Wistar (m)  Nakagawa and
10, 30) training Takashima
(1997)
CGP 36742 IP, 40 m pre- BALB/c mice  Sunyer et al.
(150) training (m) (2007)
CGP 36742 IP, 40 m pre- C57BL/6J mice  Sunyer et al.
(150) training (m) (2007)
CGP 36742 IP, 40 m pre- CD1 mice (m)  Sunyer et al.
(150) training (2007)
CGP 36742 IP, 40 m pre- CF1 mice (m)  Sunyer et al.
(150) training (2007)

93
Table 4 (continued) Summary of the effect of GABAB ligands on Morris water maze
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
CGP 36742 IP, 40 m pre- DBA/2 mice (m)  Sunyer et al.
(150) training (2007)
CGP 36742 IP, 40 m pre- OF1 mice (m)  Sunyer et al.
(150) training (2007)
CGP 36742 IP, 40 m pre- OF1 mice (m)  Sunyer et al.
(150) training (2009b)
CGP 46381 IP, 20 m pre- Sprague-Dawley  Brucato et al.
(100) training/pre-test (f) (1996)
CGP 55845 (1 Intra-EC, 15 m Sprague-Dawley  P.-Y. Deng et al.
ug) pre-training (m) (2009)

x x RGS7-/- (m/f)  Ostrovskaya et

al. (2014)
Bold = Effective concentration; (m) = male; (f) = female;  = improved;  = impaired;  = Unchanged; Pre-
training = before acquisition, before trial not specifically a recall trial; Pre-test = before recall trial; Post-
training = after acquisition or trial not specifically a recall trial; IP = intraperitoneal; PO = per os/oral; m =
minutes; h = hours; dH = dorsal hippocampus; EC = entorhinal cortex; ligand concentrations are in mg/kg
unless otherwise noted

Table 5 Summary of the effect of GABAB ligands on radial arm maze

Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Baclofen (2, 4) IP, 15 m pre-test CD1 mice (m)  Carletti et al. (1993)

Baclofen (0.125, SC, 20 m pre-test Sprague-Dawley  Levin et al. (2004)

0.25) (f)
Baclofen (0.5, 1) SC, 20 m pre-test Sprague-Dawley  Levin et al. (2004)
(f)
Baclofen (1.25, 2.5) SC, 20 m pre-test Fischer 344 (m)  Sidel et al. (1988)

Baclofen (0.75, 1.5, 3 Intra-S, post- Sprague-Dawley  Stackman and Walsh

nmol) training/60 m (m) (1994)
pre-test
CGP 35348 (12.5, 25, IP, 20-30 m pre- Long-Evans (m)  Chan et al. (2006)
50, 100) training

94
 CGP 35348 (12.5, 25, IP, 30 m pre- Long-Evans (m)  Staubli et al. (1999)
50, 100, 200, 300) training

CGP 46381 (10, 30, IP, 20 m pre-test Sprague-Dawley  Brucato et al. (1996)
100) (f)
CGP 36742 (1, 10, IP, 15 m pre-test CD1 mice (m)  Carletti et al. (1993)
100)
CGP 36742 (150) IP, post-training Long-Evans (m)  Helm et al. (2005)

CGP 36742 (6, 30, IP, 40 m pre- Long-Evans (m)  Helm et al. (2005)
150) training
x x Overexpressing  Stewart et al. (2009)
B1b (m)
x x Overexpressing  Y. Wu et al. (2007)
B1a
Bold = Effective concentration; (m) = male; (f) = female;  = improved;  = impaired;  = Unchanged; Pre-
training = before acquisition, before trial not specifically a recall trial; Pre-test = before recall trial; Post-
training = after acquisition or trial not specifically a recall trial; IP = intraperitoneal; SC = subcutaneous; m =
minutes; S = septum; ligand concentrations are in mg/kg unless otherwise noted

95
Table 6: Summary of the effect of GABAB ligands on working memory
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Baclofen (0.01, 0.05, Intra-NBM, pre- Sprague-Dawley  DeSousa et al. (1994)
0.1 ug) training (m)
Baclofen (2.5, 5, 7.5) IP, 10 m pre-test C57BL/6J mice  Escher and Mittleman
(f) (2004)
Baclofen, (2.5, 5, IP, 10 m pre-test DBA/2 mice (f)  Escher and Mittleman
7.5) (2004)
Baclofen (0.05, 0.1, Intra-MS, 15 m Sprague-Dawley  Erickson et al. (2006)
1, 2, 3 nmol) pre-training (m)
Baclofen (0.03, 0.1, Intra-MD, 10 m Sprague-Dawley  Romanides et al. (1999)
0.3 nmol) pre-test (m)
Baclofen (0.03, 0.1, Intra-VTA, 10 m Sprague-Dawley  Romanides et al. (1999)
0.3 nmol) pre-test (m)
CGP 55845 (0.01, IP, 40 m pre- Fischer 344 (m)  Bañuelos et al. (2014)
0.1) training
CGP 55845 (0.2, 0.6, Intra-mPFC Fischer 344 (m)  Bañuelos et al. (2014)
2 umol)
CGP 55845 (0.5) IP, 2-3 h pre- B6/C3H mice  Kleschevnikov et al.
training (m) (2012a)
Phaclofen (1 ug) Intra-NBM, pre- Sprague-Dawley  DeSousa et al. (1994)
test (m)
Phaclofen (10, 20, IP, 10 m pre-test C57BL/6J mice  Escher and Mittleman
30) (f) (2004)
Phaclofen (10, 20, IP, 10 m pre-test DBA/2 mice (f)  Escher and Mittleman
30) (2004)
Saclofen (5, 10, 20, Intra-DG, 15 m Sprague-Dawley  Q.-Y. Liu et al. (2014)
40 uM) pre-training (m)
x x B1a-/- (m)  Jacobson et al. (2007)
x x B1b-/- (m)  Jacobson et al. (2007)
Bold = Effective concentration; (m) = male; (f) = female;  = improved;  = impaired;  = Unchanged; Pre-
training = before acquisition, before trial not specifically a recall trial; Pre-test = before recall trial; IP =
intraperitoneal; m = minutes; h = hours; NBM = nucleus basalis magnocellularis; MS = medial septum; MD =
mediodorsal thalamus; VTA = ventral tegmental area; mPFC = medial prefrontal cortex; DG = dentate gyrus;
ligand concentrations are in mg/kg unless otherwise noted

96
Table 7 Summary of the effect of GABAB ligands on conditioned fear
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Baclofen (3, 10, IP, post-training CD1 mice (m)  Castellano et al.
30) (1989)
Baclofen (10) IP, 120 m post- CD1 mice (m)  Castellano et al.
training (1989)
Baclofen (2) IP, 15 m pre- Sprague-Dawley  Heaney et al.
training (m) (2012)
Baclofen (2) IP, 15 m pre- Sprague-Dawley  Heaney et al.
extinction (m) (2012)
Baclofen (0.5, IP, 30 m pre- Wistar (m)  X. Li et al.
1.5, 2.5) training (2013)
Baclofen (0.4, IP, 30 m pre- Wistar (m)  X. Li et al.
0.9, 1.25) training (2015)
BHF 177 (10, PO, 60 m pre- Wistar (m)  X. Li et al.
20, 40) training (2013)
BHF 177 (10, PO, 60 m pre-  X. Li et al.
20, 40) training (2015)
Wistar (m)
CGP 44532 SC, 15 m pre- Wistar (m)  X. Li et al.
(0.065, 0.125, training (2015)
0.25)
CGP 55845 (0.5) IP, 2-3 h pre- B6/C3H mice  Kleschevnikov et
training (m) al. (2012a)
Phaclofen (0.3) IP, 15 m pre- Sprague-Dawley  Heaney et al.
training (m) (2012)
Phaclofen (0.3) IP, 15 m pre- Sprague-Dawley  Heaney et al.
extinction (m) (2012)
x x B1a-/-  Cullen et al.
(2014)
x x B1a-/- (m)  Shaban et al.
(2006)
x x B1b-/- (m)  Shaban et al.
(2006)

97
Table 7 (continued) Summary of the effect of GABAB ligands on conditioned fear
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
x x RGS7-/- (m/f)  Ostrovskaya et
al. (2014)
x x S783A knockin  Terunuma et al.
(m) (2014)
Bold = Effective concentration; (m) = male; (f) = female;  = improved;  = impaired;  = Unchanged; Pre-
training = before acquisition, before trial not specifically a recall trial; Pre-extinction = before extinction
training; Post-training = after acquisition or trial not specifically a recall trial; IP = intraperitoneal; SC =
subcutaneous; PO = per os/oral; m = minutes; ligand concentrations are in mg/kg

Table 8 Summary of the effect of GABAB ligands on conditioned taste aversion

Route, time of
Ligand (Concentration) Species (sex) Effect Reference
administration
Baclofen (2, 3) IP, post- Sprague- I Wilson et al.
training Dawley (m/f) (2011)
x x B1a-/- (m)  Jacobson et
al. (2006)
x x B1b-/- (m)  Jacobson et
al. (2006)

Bold = Effective concentration; (m) = male; (f) = female;  = impaired; I = induced; Post-training = after
acquisition or trial not specifically a recall trial; IP = intraperitoneal; ligand concentrations are in mg/kg

98
Table 9 Summary of the effect of GABAB ligands on conditioned place preference
Route, time of
Ligand (Concentration) Species (sex) Effect Reference
administration
Baclofen (1, 2.5) SC, post- C57BL/6J  Heinrichs et al.
extinction mice (m) (2010)
Baclofen (1, 2.5) SC, pre- C57BL/6J  Heinrichs et al.
extinction mice (m) (2010)
Baclofen (1, 2.5) SC, pre-training C57BL/6J  Heinrichs et al.
mice (m) (2010)
Baclofen (1, 2.5) SC, post- C57BL/6J  Heinrichs et al.
training mice (m) (2010)
Baclofen (0.1, 0.5 Intra-mRN, pre- Wistar (m) I Shin and
mM) training Ikemoto
(2010)
Baclofen (0.1, 0.5 Intra-dRN, pre- Wistar (m) I Shin and
mM) training Ikemoto
(2010)
Baclofen (2) IP, post-training Sprague-  Voigt et al.
Dawley (m) (2011a)
Baclofen (0.5, 1, 2 ug) Intra-CA1, 5 m Wistar (m)  Zarrindast et
pre-training al. (2006a)
Baclofen (0.5, 1, 2 ug) Intra-CA1, 5 Wistar (m)  Zarrindast et
min pre-test al. (2006a)
CGP 7930 (30) IP, post-training Sprague-  Voigt et al.
Dawley (m) (2011b)
Fendiline (5) IP, post- Sprague-  Voigt et al.
reconditioning Dawley (m) (2014)
Fendiline (5) IP, 10 d post- Sprague-  Voigt et al.
training Dawley (m) (2014)
GS 39783 (30) IP, post-training Sprague-  Voigt et al.
Dawley (m) (2011b)
Phaclofen (1, 2, 3 ug) Intra-CA1, 5 m Wistar (m)  Zarrindast et
pre-training al. (2006a)
Phaclofen (1, 2, 3 ug) Intra-CA1, 5 m Wistar (m)  Zarrindast et
pre-test al. (2006a)

99
Table 9 (continued) Summary of the effect of GABAB ligands on conditioned place preference
Route, time of
Ligand (Concentration) Species (sex) Effect Reference
administration
x x B1a-/- (m)  DR Jacobson et al.
(2016)
x x B1b-/- (m)  DR Jacobson et al.
(2016)
Bold = Effective concentration; (m) = male;  = increased;  = decreased;  = Unchanged; I = induced; DR =
drug response; Pre-training = before acquisition, before trial not specifically a recall trial; Pre-test = before
recall trial; Post-training = after acquisition or trial not specifically a recall trial; Pre-extinction = before
extinction; Post-extinction = after extinction; Post-reconditioning = after reconditioning; IP = intraperitoneal;
SC = subcutaneous; m = minutes; mRN = median raphe nuclei; dRN =dorsal raphe nuclei; ligand
concentrations are in mg/kg unless otherwise noted

Table 10 Summary of the effect of GABAB ligands on novel object recognition and location
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Novel object recognition
Baclofen (0.5) IP, post- Wistar (m)  Car and Wiśniewski
training, 60 m (1998)
pre-test
Baclofen (12.5, IP, 19 h pre- Sprague-  C.-J. Li et al. (2014)
25) training Dawley (m)
Baclofen Intra-CA1, NMRI mice  Khanegheini et al. (2015)
(0.002, 0.02, 0.2 post-training (m)
ug)
Baclofen (0.5, IP, 30 m pre- Sprague-  Pitsikas et al. (2003)
2, 4) training Dawley (m)
Baclofen (0.5, IP, 30 m post- Sprague-  Pitsikas et al. (2003)
2, 4) training Dawley (m)
CGP 35348 IP, post- Sprague-  Pitsikas et al. (2003)
(100, 300) training Dawley (m)
CGP 55845 IP, 2-3 h pre- B6/C3H mice  Kleschevnikov et al.
(0.5) training (m) (2012a)
Phaclofen Intra-CA1, NMRI mice  Khanegheini et al. (2015)
(0.002, 0.02, 0.2 post-training (m)
ug)
x x B1a-/-  Cullen et al. (2014)
x x B1a-/- (m)  Jacobson et al. (2007)
x x B1a-/- (m)  Vigot et al. (2006)

100
 x x B1b-/- (m)  Jacobson et al. (2007)
-/-
x x B1b (m)  Vigot et al. (2006)
-/-
x x RGS7 (m/f)  Ostrovskaya et al. (2014)
x x S783A  Terunuma et al. (2014)
knockin (m)

Table 10 (continued) Summary of the effect of GABAB ligands on novel object recognition and
location
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Novel object location
Baclofen Intra-CA1, NMRI mice  Khanegheini et al. (2015)
(0.002, 0.02, 0.2 post-training (m)
ug)
CGP 55845 IP, 2-3 h pre- B6/C3H mice  Kleschevnikov et al.
(0.5) training (m) (2012a)
Phaclofen Intra-CA1, NMRI mice  Khanegheini et al. (2015)
(0.002, 0.02, 0.2 post-training (m)
ug)
x x B1a-/-  Cullen et al. (2014)
x x S783A  Terunuma et al. (2014)
knockin (m)

Bold = Effective concentration; (m) = male; (f) = female;  = impaired;  = Unchanged; Pre-training = before
acquisition, before trial not specifically a recall trial; Pre-test = before recall trial; Post-training = after
acquisition or trial not specifically a recall trial; IP = intraperitoneal; m = minutes; h = hours; ligand
concentrations are in mg/kg unless otherwise noted

101
Table 11 Summary of the effect of GABAB ligands on Barnes maze, conditional space color
task, and social recognition
Ligand Route, time of
Species (sex) Effect Reference
(Concentration) administration
Barnes maze
Baclofen (0.5, IP, 30 m pre- C57BL/6J mice  X. Li et al.
1.5, 2.5) training (m) (2013)
Baclofen (0.5, IP, 30 m pre-test C57BL/6J mice  X. Li et al.
1.5, 2.5) (m) (2013)
BHF 177 (10, PO, 60 m pre- C57BL/6J mice  X. Li et al.
20, ) training (m) (2013)
BHF 177 (10, PO, 60 m pre- C57BL/6J mice  X. Li et al.
20, 40) test (m) (2013)
x x S783A knockin  Terunuma et al.
(m) (2014)
Conditional space color task
CGP 36742 (0.5) PO, 60 m pre- Rhesus monkey  Mondadori et al.
training (m) (1993)
Social recognition
CGP 36742 (3) PO, 60 m pre- Sprague-Dawley  Mondadori et al.
training (m) (1993)
CGP 36742 PO, 120 m pre- Sprague-Dawley  Mondadori et al.
(0.003, 0.03, 3, training (m) (1996a)
30, 300)
Bold = Effective concentration; (m) = male;  = improved;  = impaired;  = Unchanged; Pre-training =
before acquisition, before trial not specifically a recall trial; Pre-test = before recall trial; IP = intraperitoneal;
PO = per os/oral; m = minutes; ligand concentrations are in mg/kg

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