AUTHOR’S COPY | AUTORENEXEMPLAR
Rev. Neurosci., Vol. 22(3): 365–371, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/RNS.2011.024
Spontaneously hypertensive rat (SHR) as an animal model for
ADHD: a short overview
Alfredo Meneses1,*, Georgina Perez-Garcia, Teresa
Ponce-Lopez1, Ruth Tellez1, Andrea Gallegos-Cari and
Carlos Castillo2,*
1
Department of Pharmacobiology, CINVESTAV, Tenorios
235, Granjas Coapa, Mexico City 14330, Mexico
2
Escuela Superior de Medicina, Instituto Politécnico
Nacional, Plan de San Luis y Díaz Mirón, Colonia Santo
Tomás, México City 11340, México
*Corresponding authors
e-mail: ameneses@msn.com; drcarloscastillo@hotmail.com
Abstract
Diverse studies indicate that attention-deficit hyperactivity
disorder (ADHD) is associated with alterations in encoding
processes, including working or short-term memory. Some
ADHD dysfunctional domains are reflected in the spontane-
ously hypertensive rat (SHR). Because ADHD, drugs and
animal models are eliciting a growing interest, hence the
aim of this work is to present a brief overview with a focus
on the SHR as an animal model for ADHD and memory
deficits. Thus, this paper reviews the concept of SHR as a
model system for ADHD, comparing SHR, Wistar-Kyoto and
Sprague-Dawley rats with a focus on the hypertension level
and working, short-term memory and attention in different
behavioral tasks, such as open field, five choice serial reac-
tion time, water maze, passive avoidance, and autoshaping. In
addition, drug treatments (d-amphetamine and methylpheni-
date) are evaluated.
Keywords: attention; attention-deficit hyperactivity disorder
(ADHD); autoshaping; d-amphetamine; hyperactivity; long-
term memory (LTM); memory; rats; short-term memory
(STM); spontaneously hypertensive rat (SHR); Sprague-
Dawley; Wistar-Kyoto.
Introduction
Growing interest on memory dysfunction in diverse dis-
orders, including Alzheimer ’s disease, schizophrenia,
Parkinson disease, diabetes, attention-deficit hyperactiv-
ity disorder (ADHD), post-traumatic stress disorder, etc.,
suggests that memory is either a promiscuous or specific
function of the brain. Wherever the nature and function of
this cognitive process might be, the study of memory for-
mation and diverse brain disorders has been producing key
information. In this regard, animal models are very impor-
tant, particularly as animal models for, not of, psychiatric
AUTHOR’S COPY | AUTORENEXEMPLAR
disorders (Millan, 2008). ADHD represents a focal point in
this context.
Modeling ADHD
Interestingly, a Medline search (September, 2010) for ‘ADHD
and drugs and animal models’ yielded 71 papers, including
22 reviews. More recently (March or April, 2011) the same
phrasing elicited 77 or 81 papers, including 23 or 24 reviews.
As regarding the latter there are many excellent papers, and
hence the aim of this work is to present a brief overview with a
particular focus on the spontaneously hypertensive rat (SHR)
as an animal model for ADHD. Hence, available evidence is
analyzed and discussed. Russell (2007) summarized that con-
sistent with ADHD being a developmental disorder, animal
models are either genetic (SHR), dopamine transporter (DAT)
knock-out mice, SNAP-25 mutant mice, mice expressing a
mutant thyroid receptor or have suffered an insult to the cen-
tral nervous system during the early stages of development
(anoxia, 6-hydroxydopamine). By contrast, neuropsychologi-
cal and imaging studies indicate that ADHD is associated with
alterations on information encoding processes such as those
observed on children with these conditions (Denckla, 1996).
The dysfunctional areas identified by diagnostic schemes
include executive and attention-related abilities (poor concen-
tration), increased motor activity (restlessness), and cognitive
and behavioral impulsivity (ill-considered responses) (Oades
et al., 2005). ADHD alterations include deficit in behavioral
inhibition (Barkley, 1997), prefrontal cortex (PFC) and to its
striatum connections (Brennan and Arnsten, 2008), dysfunc-
tion in dopaminergic, noradrenergic (Oades et al., 2005), cho-
linergic (Terry et al., 2000) and serotonergic pathways (Wilens
et al., 2008). It should be noted that approximately one-half of
ADHD patients could have working memory problems (Paule
et al., 2000) and as a group variability is constant.
ADHD and animal models
Some ADHD characteristic symptoms have been observed in
animal models (Paule et al., 2000), including the SHR, which
has been proposed as an animal model for ADHD (Oades,
1987; Wultz et al., 1990; Paule et al., 2000; Sagvolden, 2000;
Adriani et al., 2003; Russell, 2003; nevertheless, see van
den Bergh et al., 2006; Ferguson et al., 2007; Robertson et
al., 2008) for its characterization as a disorder (Oades, 1987;
Russell, 2000; Sagvolden, 2000; Sagvolden et al., 2005;
Sagvolden and Xu, 2008), and to determine memory altera-
tions related to hypertension (Meneses and Hong, 1998; Terry
et al., 2000), but not exclusively. Importantly, Wistar-Kyoto
 AUTHOR’S COPY | AUTORENEXEMPLAR
366 A. Meneses et al.
(WKY) rats are considered the control inbreed strain against
SHR, and Sprague-Dawley (SD) rats are considered as an
outbreed strain with different genetic backgrounds (Oades,
1987; Sagvolden, 2000; Russell, 2007). Actually male SD rats
with chronic hypertension showed that severe hypertension
for over 10 months is not sufficient to impair spatial learn-
ing and memory in the water maze in otherwise normal rats
(Kadish et al., 2001). And an animal model of ADHD is repre-
sented by SD-derived Naples High Excitability rats (Viggiano
et al., 2002, 2003). Likewise, male middle-aged WKY and
SHR groups chronically treated with nimodipine (a calcium
channel blocker) showed improved memory relative to their
control groups, whereas in the latter the drug decreased hyper-
tension and maintained it at normal levels during 4 weeks, in
the former it worked only during the first 2 weeks (Meneses et
al., 1997; Meneses and Hong, 1998). In another study, it was
observed that acute hypertension in male rats induced by the
deoxycorticosterine acetate-salt method produced impairment
of short-term memory (STM) in the passive avoidance task,
but did not affect spatial learning and memory in the water
maze task (Ghavipanjeh et al., 2010). SHR features hyperac-
tivity, impulsivity, poor sustained attention and learning and
memory (Meneses et al., 1996; Meneses and Hong, 1998;
Diana, 2002; Heal et al., 2008; Meneses et al., 2009; Wells et
al., 2010; but see Robertson et al., 2008). SHR also presents
disturbances in glutamate, dopamine and norepinephrine func-
tion, which parallel evidence that ADHD patients could have
defects on neuronal circuits required for reward-guided asso-
ciative learning and memory formation (Oades et al., 2005;
Heal et al., 2008; Wells et al., 2010; but see Robertson et al.,
2008), including dopamine and norepinephrine release and
impaired second messenger systems (Russell, 2000).
SHR and memory tasks
Operant behavioral tasks modeling learning, STM and simple
discriminations have been useful to detect behavioral features
of ADHD and normalization of performance on working mem-
ory (WM) and STM by stimulant drugs such as methylpheni-
date (Paule et al., 2000). Similarly, open field test, Pavlovian/
instrumental autoshaping (Meneses and Hong, 1998) and spa-
tial memory in the water maze (Terry et al., 2000) tasks have
been useful to detect the effects of drugs on adult male SHRs.
For example, in the water maze, autoshaping (Meneses et al.,
1997) and open field tests (Heal et al., 2008; Wells et al., 2010),
with 3, 6, 9, 12, 18, or 24 months (Meneses et al., 1997) or
3 months (Heal et al., 2008; Wells et al., 2010) old male SHRs,
have shown an age-related impairment on learning, memory,
and spontaneous locomotor activity relative to normotensive
WKY saline rats. Even male SHR and WKY rats have shown
memory deficits relative to SD rats in the water maze task
(Wells et al., 2010) or SD rats in an autoshaping test (Meneses
et al., 2011a). Although the memory deficits are partially or
completely reversed by the calcium channel blocker nimo-
dipine in autoshaping task (Meneses et al., 1997), uridine and
choline supplementation normalizes attention of SHR in the
five choice serial reaction time (5-CSRT) test and improves
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water maze acquisition in both WKY and SHR rats (De Bruin
et al., 2003). Certainly, the uses of the WKY strain as the ‘con-
trol’ for the SHRs have been questioned (Terry et al., 2000;
Ferguson et al., 2007; Robertson et al., 2008). Although SHRs
are a genetic model with neural disturbances, they are not nec-
essarily or exclusively related to hypertension per se (Meneses
and Hong, 1998; Diana, 2002; De Bruin et al., 2003).
WKY and SHR behavioral characteristics
Interestingly, questions have been raised about the extent to
which SHRs represent ADHD (van den Bergh et al., 2006),
and that WKY rats are not appropriated controls of SHRs in
numerous behavioral features (Clements and Wainwright,
2006; Ferguson et al., 2007; Grundt et al., 2009), including
locomotor activity. Indeed, whereas SHRs are hyperactive,
WKY rats are hypoactive (Alsop, 2007), even the latter have
been used as an animal model of depression (Robertson et al.,
2008). In addition, SHRs regarding WKY rats present sev-
eral genetic and neurochemical differences (Johnson et al.,
1995; Drolet et al., 2002; see also Grundt et al., 2009). For
instance, SHRs have a Y chromosome locus that increases
blood pressure and this locus requires an androgen receptor
and testosterone for maximum expression as well as having
significantly higher steroid sulfatase activity in testes, adre-
nal gland, liver, and hypothalamus (Johnson et al., 1995).
Sometimes even WKY rats could present hypertension
(Louis and Howes, 1990) and even though medial temporal
lobe functioning appears to be normal in SHRs exhibiting an
ADHD-like phenotype, WKY hypertensive (WKHT) male
rats display both hippocampal functioning deficits and signs
of bilateral hippocampal cell loss (Wells et al., 2010).
Memory, behavioral tasks and cognitive demand
Deficits in temporal processing have been implicated in
ADHD. Thus, in a study, adult males and females of SHR,
WKY and SD strains were compared in two timing tasks,
temporal response differentiation (TRD) and differential rein-
forcement of low rates (DRL) (Ferguson et al., 2007), indicat-
ing that strains did not differ in task acquisition; however, the
steady state of TRD and DRL performance of the SHR and
WKY strains was less accurate, which was related to increased
burst (non-timing related) responses. Subsequently, methyl-
phenidate (1.0–12.0 mg/kg) or d-amphetamine (0.1–2.0 mg/kg)
pretesting treatment showed that both drugs disrupted non-
significantly TRD and DRL performances. Strain differences
were generally maintained throughout the drug and extinction
sections of the study. Ferguson et al. (2007) concluded that their
results do not support continued use of the SHR as a model for
ADHD. Additionally, Robertson et al. (2008) showed that the
STM capabilities of male SHRs, that are necessary for WM
performance, appear to be intact, and the evidence of executive
deficits related to WM functions was limited (observable only
in the massed trials and were also evident in the WKY control
group) in the radial water maze configured as a T-maze and
delayed matching-to-place task. Once again, these findings do
 AUTHOR’S COPY | AUTORENEXEMPLAR
not support the use of SHRs as a model to address the con-
dition termed ADHD (Robertson et al., 2008). Nonetheless,
Sagvolden (2000), who pioneered the testing of SHRs in
behavioral and memory tasks, has highlighted that a good
model mimics the fundamentals of the behavioral characteris-
tics of ADHD, conforms to a theoretical rationale for it and is
able to predict aspects of ADHD. Importantly, although other
strains and species could be hyperactive and/or show atten-
tion deficits following genetic, environmental or pharmaco-
logical interventions, the SHRs are presently the only strain
that have shown the major behavioral symptoms of ADHD,
suggesting that this does not mean that research with other
models cannot provide valuable information (Sagvolden and
Xu, 2008). For instance, male SHRs, WKY and SD rats were
assessed in spatial memory as measured of their performance
in a win-shift version of the water radial arm maze and the
results showed that all strains made more errors on trial 4,
when the mnemonic demand was highest, and they showed a
similar response when the delay was increased from 60 s to
2 h on week 3 (Clements and Wainwright, 2006). Both SHRs
and WKY rats made more reference memory errors than SD
rats; however, SHRs showed minimal improvement over
weeks. According to the same authors, the increase in errors
could be due to a greater inclination of SHRs and WKY
rats to use a chaining strategy of entering consecutive arms
than SD rats. Furthermore, the number of incomplete arm
entries into reference memory arms decreased over weeks
in WKY and SD rats, but increased in SHRs, suggesting an
increased impulsivity of SHRs at the later stages of testing.
Although, based on number of errors, the data indicate that
SHRs could have memory deficits, the data relating to arm
entries suggest that the minimal improvement in SHRs over
weeks could have been due to greater impulsivity in the later
weeks, rather than defective memory. Thus, these findings
are consistent with SHRs having impairments with a selec-
tion of appropriate behavioral responses in a goal-directed
task (Clements and Wainwright, 2006). Moreover, male
SHRs vs. WKY and SD rats were compared in the operant
delayed non-matching-to-position (DNMTP) test for study-
ing STM, 5-CSRT task for assessing selective visual atten-
tion processes, and the water maze for spatial learning and
mnemonic capabilities, and the findings revealed impaired
attention (De Bruin et al., 2003). Both the SHRs and WKY
rats showed deficits in spatial learning when compared with
the SD rats. Thus, SHRs have a deficiency in visual selective
attention and spatial learning.
Spatial vs. habit learning and memory
Similarly, the male WKHT (hypertensive WKY) rats, SHR
and WKY strains show similar levels of amygdala-related
stimulus-reward learning during conditioned cue preference
testing (Wells et al., 2010). In the ambiguous T-maze task,
which dissociates between spatial (i.e., hippocampus-depen-
dent) and habit learning (i.e., hippocampus-independent),
WKHT rats significantly used more a response (indicative
of habit learning) vs. a place (indicative of spatial learning)
AUTHOR’S COPY | AUTORENEXEMPLAR
ADHD, SHR, D -amphetamine and memory 367
strategy than SHRs or WKY rats during an early probe test
on day 8. During a later probe test on day 24, WKY rats pro-
gressed significantly from using a place strategy to a response
strategy. Throughout all probe tests, special strategy was used
predominately by SHRs and a habit strategy by WKHT rats
(Wells et al., 2010). Thus, SHRs exhibited deficits in dorsal
striatum-related habit learning, whereas WKHT rats exhib-
ited deficits in hippocampus-related spatial learning (Wells
et al., 2010). It should be nevertheless noted that when the
integration of information derived from sign (i.e., the action
of stimulus-stimulus, classical conditioning) and goal track-
ing (i.e., response-stimulus, instrumental/operant condition-
ing) settings (Meneses, 2003; Tellez and Meneses, 2009;
Tellez et al., 2010; Meneses et al., 2011a,b,c) are tested on an
autoshaping task, the adult male SHR-saline group showed
poor STM and long-term memory (LTM) relative to SD and
WKY vehicle rats (Meneses et al., 2011a). By contrast, male
SD and WKY rats treated with d-amphetamine displayed bet-
ter STM and LTM, compared with SD-vehicle, WKY-vehicle
or SHR-d-amphetamine groups; and the latter showed better
STM and LTM relative to the SHR-vehicle group (Johnson et
al., 1995). That this autoshaping protocol reflects STM and
LTM is supported by the evidence that it engages hippocam-
pus (mediating declarative memory) and striatum (mediating
stimulus-response ‘habit’ formation) (Meneses, 2003; Tellez
and Meneses, 2009; Tellez et al., 2010), respectively, and by
the forgetting curve (i.e., decreased performance), observable
when autoshaping training and testing sessions are interrupted
by a period larger than 48–72 h (Tellez and Meneses, 2009).
Likewise, the contingent or 6 h later (following training), inhi-
bition of hippocampal protein synthesis or new mRNA did
not affect autoshaping STM but it specifically impaired LTM
performance (Izquierdo et al., 1998; Meneses, 2003, 2007a;
Tellez and Meneses, 2009; Tellez et al., 2010; Meneses et al.,
2011b,c); therefore, the procedure seems to be valid in the
temporal and molecular bases for STM and LTM study. As
autoshaping STM and LTM are mediated by the PFC and hip-
pocampus, respectively (Meneses, 2003; Liy-Salmeron and
Meneses, 2007, 2008; Meneses, 2007a,b; Tellez and Meneses,
2009; Tellez et al., 2010; Meneses et al., 2011b,c), which is
consistent with the evidence that SHRs reflect diminished
habituation and severe deficits in attention, learning, and
memory (see above), which are probably related to (at least)
a dysfunctional PFC. Nevertheless, when WM was assessed
in the water maze with different strategic demands, including
the delayed matching-to-place task (DMP), the performance
of male SHRs did not differ from that of either of SD or WKY
rats (Robertson et al., 2008). As already mentioned, Robertson
et al. (2008) concluded that their findings do not provide fur-
ther support of STM impairments in the SHRs, and hence this
strain is not appropriated in the study of ADHD in humans.
Notwithstanding, consistent with the notion of SHRs show-
ing STM and LTM impairments, others authors have reported
that this strain present poor memory in several memory tasks,
including the water maze (Terry et al., 2000), novel object
recognition (Tian et al., 2009), STM in the DMP version of
the Morris water maze (Clements et al., 2003), odor-delayed
win-shift (nonspatial working and reference memory), win-
 AUTHOR’S COPY | AUTORENEXEMPLAR
368 A. Meneses et al.
stay (habit learning), and attentional set-shifting (Kantak et
al., 2008) and other tasks (Sagvolden and Xu, 2008). Taken
together, these data support the notion that SHRs have poor
STM and LTM relative to (in increasing order) WKY<SD rats
and provide further support to the notion that this strain repre-
sents a useful tool in the study of memory deficits on ADHD.
Certainly, to clarify the discrepant findings further studies are
necessary, which would be very insightful to investigate, e.g.,
loci and mechanisms.
Locus and memory processes
That the above mentioned d-amphetamine improvement on
autoshaping STM and LTM might occur via stimulation of
(at least) the PFC is supported by evidence that projections
present in this area (de Almeida et al., 2008; González-Burgos
and Feria-Velasco, 2008) play an important role in the pro-
cessing of mnemonic information (de Almeida et al., 2008;
González-Burgos and Feria-Velasco, 2008; Olvera-Cortés
et al., 2008), particularly STM (Liy-Salmeron and Meneses,
2008). Inhibition of protein and mRNA synthesis on the PFC
prevents STM without affecting LTM (Liy-Salmeron and
Meneses, 2007), and as already mentioned SHRs present
poor STM and LTM regarding SD and WKY rats, and acute
post-training d-amphetamine administration reverses such an
effect (Meneses et al., 2011a). Hence, STM and PFC seem
to be affected in SHRs, which might be due to functional
and/or structural changes. For instance, microarray analysis
revealed that male SHRs relative to WKY rats up- and down-
regulated genes in the PFC (Qiu et al., 2010), including genes
in charge of monoamines, signal transduction, etc. Inasmuch
as WM depends upon the integrity of the PFC (Solanto,
1998; Castner et al., 2004; Kibby and Cohen, 2008; Qiu et
al., 2010) and as this brain structure is dysfunctional in sub-
jects with ADHD (Stevenson and Wolraich, 1989; Kibby and
Cohen, 2008); hence, poor STM and dysfunctional PFC in
SHRs would be useful to model parts of ADHD. Concerning
d-amphetamine and memory tasks, it should be noted that the
nature of memory task, timing, dosing and locus of admin-
istration determine if it produces improvement, impairment
or no effects (Podolski, 1998; Moncada and Viola, 2007).
Actually, post-training administration of d-amphetamine
produces a dose-dependent enhancement of memory on
autoshaping (Oscos et al., 1985, 1988; Rodriguez et al., 2008),
retention in a passive avoidance (Beatty and Rush, 1983) or
selectively enhances spatial memory (Calabrese, 2001). The
pharmacological, neural, and molecular mechanisms remain
unclear and future research should also explore their neural
and cognitive mechanisms. For instance, propranolol alone
has no effects on retention, but antagonizes the d-amphet-
amine memory-enhancing effect and elevates noradrenaline
release (Lee and Ma, 1995). It should nevertheless be noted
that propranolol impaired working and emotional memory
(Chamberlain et al., 2006); indeed, it is useful in the treatment
of post-traumatic stress disorder (Glannon, 2006). In addition,
propranolol is commonly identified as a β-adrenergic antago-
nist, it also displays affinity for 5-HT1A and 5-HT1B receptors
AUTHOR’S COPY | AUTORENEXEMPLAR
(Hoyer et al., 1994). Antagonists for these serotonergic recep-
tors could have no effects, improve memory, and/or reverse
amnesia (Meneses, 1999, 2003). The implications for this
information is more important in the context that stimulants
are currently the most common treatment for ADHD, and pre-
clinical and clinical studies (Zeeuws and Soetens, 2007) sug-
gest that methylphenidate and d-amphetamine could involve
activation of presynaptic inhibitory autoreceptors, reducing
dopaminergic and noradrenergic activity (Bymaster et al.,
2002; Rosa et al., 2008). Thus, stimulants have paradoxical
calming effects in ADHD and stimulating effects on normal
individuals, and produce hyperactivity in rats. Notably low
doses of stimulants are clinically relevant (Tian et al., 2009),
which supports the focus on attention and improves executive
function in both normal and ADHD subjects (Stevenson and
Wolraich, 1989; Arnsten, 2006). Nonetheless, in humans the
d-amphetamine-facilitatory effect on verbal memory does not
involve modulation of the initial encoding or STM processes
(Rosa et al., 2008). In the above mentioned study (Meneses et
al., 2011a), the d-amphetamine dose previously tested com-
prises the highest possible and because at 48 h all three strains
responded similarly, as a consequence, the use of lower doses
or other times would be more insightful. For instance, low
doses of methylphenidate reduce locomotor activity in rats
and increase norepinephrine and dopamine release (Arnsten,
2006) in the PFC, whereas provoking only subtle effects on
subcortical catecholamine release. Even some commonalities
between ADHD and schizophrenia highlight the functional
importance of dopaminergic and glutamatergic neurotrans-
mission dysfunction in PFC and deficit memory (Marsh and
Williams, 2006). As a consequence, several neurotransmis-
sion systems might be altered in ADHD and/or represent
viable therapeutic alternatives. Certainly, the monoamines
represent promising means of modulating PFC dysfunction to
ameliorate cognitive deficits in disorders such as ADHD and
schizophrenia (Goldman-Rakic, 1996; Robbins and Arnsten,
2009).
SHR and ADHD
As mentioned in the Introduction section, ADHD is a com-
plex central nervous system disorder characterized by
hyperactivity, inattention, and impulsivity, and SHRs do not
consistently display symptoms of ADHD across the different
tests (Chamberlain et al., 2006; van den Bergh et al., 2006);
however, this strain could be useful in the study of memory
alterations observed in ADHD patients. An important prob-
lem in this context is that WKY rats sometimes represent
a poor control group with regard to SHRs (Chamberlain et
al., 2006; van den Bergh et al., 2006). Nevertheless, SHRs
as a model of ADHD offer insights about its memory com-
ponent. Thus, WKY and SD groups treated with d-amphet-
amine display better STM and LTM (24 h) than SHR-vehicle
or SHR-amphetamine groups (Meneses et al., 2011a). In
fact, the finding that poor STM in SHRs was normalized by
d-amphetamine tends to support the link between the PFC
and memory. These results are novel in the sense that they
 AUTHOR’S COPY | AUTORENEXEMPLAR
demonstrate that associative STM and LTM are impaired in
SHRs and that d-amphetamine reversed it. Likewise, these
data to some extent confirm the previous baseline comparison
in all outlined rats on tasks assessing timing and motivation
and pretraining d-amphetamine administration (Ferguson et
al., 2007) or learning of reinforced repetitions vs. reinforced
variations (Mook and Neuringer, 1994). Perhaps, the more
relevant issue that these data illustrate is that WKY rats show
poor STM and LTM relative to SD rats, certainly WKY rats
are better than SHRs. Without a doubt SHRs represent a good
model for the study of memory deficits in ADHD, primarily
in the context of models for particular risk factors or symp-
toms, and responsiveness to specific mechanisms of drug
action or other treatment modes (Millan, 2008) or biomarkers
useful for the diagnosis of ADHD, and also for understanding
the pathological mechanisms for development of therapeutics
venues.
As different subtypes of ADHD could represent distinct
neurobehavioral disorders of childhood onset with sepa-
rate etiologies and as the SHR model has some advantages,
these fulfill some of the validation criteria (Sagvolden et
al., 2008, 2009), including memory deficits, and as a conse-
quence it seems reasonable to use this strain and appropriate
genetic and behavioral control groups. Further experiments
are necessary to test lower doses of d-amphetamine and
other drugs on SHRs and their molecular mechanisms, par-
ticularly in the context of alterations in SHRs and ADHD
related to a deficit in behavioral inhibition, dysfunctional
PFC and striatum connections, as well as dysfunctional
dopaminergic, noradrenergic, cholinergic, and serotonergic
neurotransmission. Finally, SHRs seem to be a useful tool
to model ADHD dysfunctional domains on memory.
Acknowledgments
The authors wish to thank Sofia Meneses-Goytia for revising the
English language. Our work is supported, in part, by CONACYT
grant 80060.
References
Adriani, W., Caprioli, A., Granstrem, O., Carli, M., and Laviola, G.
(2003). The spontaneously hypertensive-rat as an animal model
of ADHD: evidence for impulsive and non-impulsive subpopula-
tions. Neurosci. Biobehav. Rev. 27, 639–651.
Alsop, B. (2007). Problems with spontaneously hypertensive rats
(SHR) as a model of attention-deficit/hyperactivity disorder (AD/
HD). J. Neurosci. Methods 162, 42–48. Corrected and repub-
lished in: J. Neurosci. Methods (2007) 166, XV–XXI.
Arnsten, A.F. (2006). Stimulants: therapeutic actions in ADHD.
Neuropsychopharmacology 31, 2376–2383.
Barkley, R.A. (1997). Behavioral inhibition, sustained attention, and
executive functions: constructing a unifying theory of ADHD.
Psychol. Bull. 121, 65–94.
Beatty, W.W. and Rush, J.R. (1983). Retention deficit after d-am-
phetamine treatment: memory defect or performance change?
Behav. Neural Biol. 37, 265–275.
AUTHOR’S COPY | AUTORENEXEMPLAR
ADHD, SHR, D -amphetamine and memory 369
Brennan, A.R. and Arnsten, A.F. (2008). Neuronal mechanisms
underlying attention deficit hyperactivity disorder: the influence
of arousal on prefrontal cortical function. Ann. N. Y. Acad. Sci.
1129, 236–245.
Bymaster, F.P., Katner, J.S., Nelson, D.L., Hemrick-Luecke, S.K.,
Threlkeld, P.G., Heiligenstein, J.H., Morin, S.M., Gehlert, D.R.,
and Perry, K.W. (2002). Atomoxetine increases extracellular lev-
els of norepinephrine and dopamine in prefrontal cortex of rat: a
potential mechanism for efficacy in attention deficit/hyperactiv-
ity disorder. Neuropsychopharmacology 27, 699–711.
Calabrese, E.J. (2001). Dopamine: biphasic dose responses. Crit.
Rev. Toxicol. 31, 563–583.
Castner, S.A., Goldman-Rakic, P.S., and Williams, G.V. (2004).
Animal models of working memory: insights for targeting cogni-
tive dysfunction in schizophrenia. Psychopharmacology (Berl.)
174, 111–125.
Chamberlain, S.R., Müller, U., Blackwell, A.D., Robbins, T.W., and
Sahakian, B.J. (2006). Noradrenergic modulation of working
memory and emotional memory in humans. Psychopharmacology
(Berl.) 188, 397–407.
Clements, K.M. and Wainwright, P.E. (2006). Spontaneously hyper-
tensive, Wistar-Kyoto and Sprague-Dawley rats differ in perfor-
mance on a win-shift task in the water radial arm maze. Behav.
Brain Res. 167, 295–304.
Clements, K.M., Girard, T.A., Xing, H.C., and Wainwright, P.E.
(2003). Spontaneously hypertensive and Wistar-Kyoto rats dif-
fer in delayed matching-to-place performance and response to
dietary long-chain polyunsaturated fatty acids. Dev. Psychobiol.
43, 57–69.
de Almeida, J., Palacios, J.M., and Mengod, G. (2008). Distribution
of 5-HT and DA receptors in primate prefrontal cortex: implica-
tions for pathophysiology and treatment. Prog. Brain Res. 172,
101–115.
De Bruin, N.M., Kiliaan, A.J., De Wilde, M.C., and Broersen, L.M.
(2003). Combined uridine and choline administration improves
cognitive deficits in spontaneously hypertensive rats. Neurobiol.
Learn. Mem. 80, 63–79.
Denckla, M.B. (1996). Biological correlates of learning and atten-
tion: what is relevant to learning disability and attention-deficit
hyperactivity disorder? J. Dev. Behav. Pediatr. 17, 114–119.
Diana, G. (2002). Does hypertension alone lead to cognitive decline
in spontaneously hypertensive rats? Behav. Brain Res. 134,
113–121.
Drolet, G., Proulx, K., Pearson, D., Rochford, J., and Deschepper,
C.F. (2002). Comparisons of behavioral and neurochemical
characteristics between WKY, WKHA, and Wistar rat strains.
Neuropsychopharmacology 27, 400–409.
Ferguson, S.A., Paule, M.G., Cada, A., Fogle, C.M., Gray, E.P., and
Berry, K.J. (2007). Baseline behavior, but not sensitivity to stim-
ulant drugs, differs among spontaneously hypertensive, Wistar-
Kyoto, and Sprague-Dawley rat strains. Neurotoxicol. Teratol.
29, 547–561.
Ghavipanjeh, G.R., Alaei, H., Khazaei, M., Pourshanazari, A.A., and
Hoveida, R. (2010). Effect of acute and chronic hypertension on
short- and long-term spatial and avoidance memory in male rats.
Pathophysiology 17, 39–44.
Glannon, W. (2006). Psychopharmacology and memory. J. Med.
Ethics 32, 74–78.
Goldman-Rakic, P.S. (1996). Regional and cellular fractionation of
working memory. Proc. Natl. Acad. Sci. USA 93, 13473–13480.
González-Burgos, I. and Feria-Velasco, A. (2008). Serotonin/dop-
amine interaction in memory formation. Prog. Brain Res. 172,
603–623.
 AUTHOR’S COPY | AUTORENEXEMPLAR
370 A. Meneses et al.
Grundt, A., Grundt, C., Gorbey, S., Thomas, M.A., and Lemmer,
B. (2009). Strain-dependent differences of restraint stress-
induced hypertension in WKY and SHR. Physiol. Behav. 97,
341–346.
Heal, D.J., Smith, S.L., Kulkarni, R.S., and Rowley, H.L. (2008).
New perspectives from microdialysis studies in freely-moving,
spontaneously hypertensive rats on the pharmacology of drugs
for the treatment of ADHD. Pharmacol. Biochem. Behav. 90,
184–197.
Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P.R., Martin, G.R.,
Mylecharane, E.J., Saxena, P.R., and Humphrey, P.P. (1994).
International Union of Pharmacology classification of recep-
tors for 5-hydroxytryptamine (Serotonin). Pharmacol. Rev. 46,
157–203.
Izquierdo, I., Medina, J.H., Izquierdo, L.A., Barros, D.M., de Souza,
M.M., and Mello e Souza, T. (1998). Short- and long-term mem-
ory are differentially regulated by monoaminergic systems in the
rat brain. Neurobiol. Learn. Mem. 69, 219–224.
Johnson, M.L., Ely, D.L., and Turner, M.E. (1995). Steroid sulfatase
and the Y chromosome hypertensive locus of the spontaneously
hypertensive rat. Steroids 60, 681–685.
Kadish, I., van Groen, T., and Wyss, J.M. (2001). Chronic, severe
hypertension does not impair spatial learning and memory in
Sprague-Dawley rats. Learn. Mem. 8, 104–111.
Kantak, K.M., Singh, T., Kerstetter, K.A., Dembro, K.A., Mutebi,
M.M., Harvey, R.C., Deschepper, C.F., and Dwoskin, L.P. (2008).
Advancing the spontaneous hypertensive rat model of attention
deficit/hyperactivity disorder. Behav. Neurosci. 122, 340–357.
Kibby, M.Y. and Cohen, M.J. (2008). Memory functioning in chil-
dren with reading disabilities and/or attention deficit/hyperactiv-
ity disorder: a clinical investigation of their working memory
and long-term memory functioning. Child Neuropsychol. 14,
525–546.
Lee, E.H. and Ma, Y.L. (1995). Amphetamine enhances memory
retention and facilitates norepinephrine release from the hip-
pocampus in rats. Brain Res. Bull. 37, 411–416.
Liy-Salmeron, G. and Meneses, A. (2007). Role of 5-HT1–7 receptors
in short- and long-term memory for an autoshaping task: intra-
hippocampal manipulations. Brain Res. 1147, 140–147.
Liy-Salmeron, G. and Meneses, A. (2008). Effects of 5-HT drugs
in prefrontal cortex during memory formation and the ketamine
amnesia-model. Hippocampus 18, 965–974.
Louis, W.J. and Howes, L.G. (1990). Genealogy of the spontane-
ously hypertensive rat and Wistar-Kyoto rat strains: implications
for studies of inherited hypertension. J. Cardiovasc. Pharmacol.
16 (Suppl. 7), S1–S5.
Marsh, P.J. and Williams, L.M. (2006). ADHD and schizophrenia
phenomenology: visual scanpaths to emotional faces as a poten-
tial psychophysiological marker? Neurosci. Biobehav. Rev. 30,
651–665.
Meneses, A. (1999). 5-HT system and cognition. Neurosci. Biobehav.
Rev. 23, 1111–1125.
Meneses, A. (2003). A pharmacological analysis of an associative
learning task: 5-HT1A to 5-HT7 receptor subtypes function on a
Pavlovian/instrumental autoshaped memory. Learn. Mem. 10,
363–372.
Meneses, A. (2007a). Stimulation of 5-HT1A, 5-HT1B, 5-HT2A/2C,
5-HT3 and 5-HT4 receptors or 5-HT uptake inhibition: short- and
long-term memory. Behav. Brain Res. 184, 81–90.
Meneses, A. (2007b). Do serotonin1–7 receptors modulate short- and
long-term memory? Neurobiol. Learn. Mem. 87, 561–572.
Meneses, A. and Hong, E. (1998). Spontaneously hypertensive rats:
a potential model to identify drugs for treatment of learning dis-
orders. Hypertension 31, 968–972.
AUTHOR’S COPY | AUTORENEXEMPLAR
Meneses, A., Castillo, C., Ibarra, M., and Hong, E. (1996). Effects of
aging and hypertension on learning, memory and activity in rats.
Physiol. Behav. 60, 341–345.
Meneses, A., Terrón, J.A., Ibarra, M., and Hong, E. (1997). Effects
of nimodipine on learning in normotensive and spontaneously
hypertensive rats. Behav. Brain Res. 85, 121–125.
Meneses, A., Perez-Garcia, G., Liy-Salmeron, G., Ponce-Lopez,
T., Tellez, R., and Flores-Galvez, D. (2009). Associative learn-
ing, memory and serotonin: a neurobiological and pharmaco-
logical analysis. In: Models of Neuropharmacology. L.L. Rocha
Arrieta and V. Granados-Soto, eds. (Trivandrum, Kerala, India:
Transworld Research Network), pp. 169–182.
Meneses, A., Ponce-Lopez, T., Tellez, R., Gonzalez, R., Castillo, C.,
and Gasbarri, A. (2011a). Effects of d-amphetamine on short- and
long-term memory in spontaneously hypertensive, Wistar-Kyoto
and Sprague-Dawley rats. Behav. Brain Res. 216, 472–476.
Meneses, A., Perez-Garcia, G., Ponce-Lopez, T., Tellez, R., and
Castillo, C. (2011b). Serotonin transporter and memory.
Neuropharmacology [Epub ahead of print]; DOI:10.1016/j.
neuropharm.2011.01.018. PMID: 21276807.
Meneses, A., Pérez-García, G., Ponce-Lopez, T., and Castillo, C.
(2011c). 5-HT6 Receptor memory and amnesia: behavioral phar-
macology – learning and memory processes. Int. Rev. Neurobiol.
96, 27–47.
Millan, M.J. (2008). The discovery and development of pharma-
cotherapy for psychiatric disorders: a critical survey of animal
and translational models and perspectives for their improve-
ment. In: Animal and Translational Models for CNS Drug
Discovery, R. McArthur and F. Borsini, eds. (Amsterdam:
Elsevier), pp. 1–57.
Moncada, D. and Viola, H. (2007). Induction of long-term memory
by exposure to novelty requires protein synthesis: evidence for a
behavioral tagging. J. Neurosci. 27, 7476–7481.
Mook, D.M. and Neuringer, A. (1994). Different effects of amphet-
amine on reinforced variations versus repetitions in spontane-
ously hypertensive rats (SHR). Physiol. Behav. 56, 939–944.
Oades, R.D. (1987). Attention deficit disorder with hyperactivity
(ADDH): the contribution of catecholaminergic activity. Prog.
Neurobiol. 29, 365–391.
Oades, R.D., Sadile, A.G., Sagvolden, T., Viggiano, D., Zuddas, A.,
Devoto, P., Aase, H., Johansen, E.B., Ruocco, L.A., and Russell,
V.A. (2005). The control of responsiveness in ADHD by cate-
cholamines: evidence for dopaminergic, noradrenergic and inter-
active roles. Dev. Sci. 8, 122–131.
Olvera-Cortés, M.E., Anguiano-Rodríguez, P., López-Vázquez,
M.A., and Alfaro, J.M. (2008). Serotonin/dopamine interaction
in learning. Prog. Brain Res. 172, 567–602.
Oscos, A., Camacho, J.L., Meneses, A., and Aleman, V. (1985).
The post-trial effect of amphetamine in memory and in cerebral
protein amino acid incorporation in the rat. In: Contemporary
Psychology: Biological Processes and Theoretical Issues, J.M.
McGaugh, ed. (Amsterdam: North-Holland), pp. 123–129.
Oscos, A., Martinez, J.L., Jr., and McGaugh, J.L. (1988). Effects
of post-training d-amphetamine on acquisition of an appetitive
autoshaped lever press response in rats. Psychopharmacology
(Berl.) 95, 132–134.
Paule, M.G., Rowland, A.S., Ferguson, S.A., Chelonis, J.J., Tannock,
R., Swanson, J.M., and Castellanos, F.X. (2000). Attention defi-
cit/hyperactivity disorder: characteristics, interventions and
models. Neurotoxicol. Teratol. 22, 631–651.
Podolski, I.Ya. (1998). Possibility of “superfast” consolidation of
long-term memory. Membr. Cell Biol. 11, 743–752.
Qiu, J., Hong, Q., Chen, R.H., Tong, M.L., Zhang, M., Fei, L., Pan,
X.Q., Guo, M., Guo, X.R., and Chi, X. (2010). Gene expression
 AUTHOR’S COPY | AUTORENEXEMPLAR
profiles in the prefrontal cortex of SHR rats by cDNA microar-
rays. Mol. Biol. Rep. 37, 1733–1740.
Robbins, T.W. and Arnsten, A.F. (2009). The neuropsychopharma-
cology of fronto-executive function: monoaminergic modula-
tion. Annu. Rev. Neurosci. 32, 267–287.
Robertson, B.A., Clements, K.M., and Wainwright, P.E. (2008). The
working memory capabilities of the spontaneously hypertensive
rat. Physiol. Behav. 94, 481–486.
Rodriguez, J.S., Boctor, S.Y., Phelix, C.F., and Martinez, J.L., Jr.
(2008). Differences in performance between Sprague-Dawley
and Fischer 344 rats in positive reinforcement tasks. Pharmacol.
Biochem. Behav. 89, 17–22.
Rosa, D.V., Souza, R.P., Souza, B.R., Guimarães, M.M., Carneiro,
D.S., Valvassori, S.S., Gomez, M.V., Quevedo, J., and Romano-
Silva, M.A. (2008). DARPP-32 expression in rat brain after an
inhibitory avoidance task. Neurochem. Res. 33, 2257–2262.
Russell, V.A. (2000). The nucleus accumbens motor-limbic inter-
face of the spontaneously hypertensive rat as studied in vitro by
the superfusion slice technique. Neurosci. Biobehav. Rev. 24,
133–136.
Russell, V.A. (2003). Dopamine hypofunction possibly results from a
defect in glutamate-stimulated release of dopamine in the nucleus
accumbens shell of a rat model for attention deficit hyperactiv-
ity disorder – the spontaneously hypertensive rat. Neurosci.
Biobehav. Rev. 27, 671–682.
Russell, V.A. (2007). Neurobiology of animal models of attention-
deficit hyperactivity disorder. J. Neurosci. Methods 161, 185–
198. Corrected and republished in: J. Neurosci. Methods (2007)
166, I–XIV.
Sagvolden, T. (2000). Behavioral validation of the spontaneously
hypertensive rat (SHR) as an animal model of attention-deficit/
hyperactivity disorder (AD/HD). Neurosci. Biobehav. Rev. 24,
31–39.
Sagvolden, T. and Xu, T. (2008). Amphetamine improves poor sus-
tained attention while d-amphetamine reduces overeactivity and
impulsiveness as well as improves sustained attention in an ani-
mal model of attention-deficit/hyperactivity disorder (ADHD).
Behav. Brain Funct. 4, 3.
Sagvolden, T., Russell, V.A., Aase, H., Johansen, E.B., and Farshbaf,
M. (2005). Rodent models of attention-deficit/hyperactivity dis-
order. Biol. Psychiatry 57, 1239–1247.
Sagvolden, T., Dasbanerjee, T., Zhang-James, Y., Middleton, F., and
Faraone, S. (2008). Behavioral and genetic evidence for a novel
animal model of attention-deficit/hyperactivity disorder predom-
inantly inattentive subtype. Behav. Brain Funct. 4, 56.
Sagvolden, T., Johansen, E.B., Wøien, G., Walaas, S.I., Storm-
Mathisen, J., Bergersen, L.H., Hvalby, O., Jensen, V., Aase, H.,
Russell, V.A., et al. (2009). The spontaneously hypertensive rat
model of ADHD – the importance of selecting the appropriate
reference strain. Neuropharmacology 57, 619–626.
AUTHOR’S COPY | AUTORENEXEMPLAR
ADHD, SHR, D -amphetamine and memory 371
Solanto, M.V. (1998). Neuropsychopharmacological mechanisms of
stimulant drug action in attention-deficit hyperactivity disorder: a
review and integration. Behav. Brain Res. 94, 127–152.
Stevenson, R.D. and Wolraich, M.L. (1989). Stimulant medi-
cation therapy in the treatment of children with attention
deficit hyperactivity disorder. Pediatr. Clin. North Am. 36,
1183–1197.
Tellez, R. and Meneses, A. (2009). Drug treatment and age differ-
entially affected memory formation and forgetting, Chicago, IL,
October 17–21, 2009. Soc. Neurosci. Abstr. 885.2.
Tellez, R., Rocha, L., Castillo, C., and Meneses, A. (2010).
Autoradiographic study of serotonin transporter during memory
formation. Behav. Brain Res. 212, 12–26.
Terry, A.V., Jr., Hernandez, C.M., Buccafusco, J.J., and Gattu, M.
(2000). Deficits in spatial learning and nicotinic-acetylcholine
receptors in older, spontaneously hypertensive rats. Neuroscience
101, 357–368.
Tian, Y., Wang, Y., Deng, Y., and Maeda, K. (2009). Methylphenidate
improves spatial memory of spontaneously hypertensive rats:
evidence in behavioral and ultrastructural changes. Neurosci.
Lett. 461, 106–109.
van den Bergh, F.S., Bloemarts, E., Chan, J.S., Groenink, L., Olivier,
B., and Oosting, R.S. (2006). Spontaneously hypertensive rats do
not predict symptoms of attention-deficit. Pharmacol. Biochem.
Behav. 83, 380–390.
Viggiano, D., Vallone, D., Welzl, H., and Sadile, A.G. (2002). The
Naples high- and low-excitability rats: selective breeding, behav-
ioral profile, morphometry, and molecular biology of the meso-
cortical dopamine system. Behav. Genet. 32, 315–333.
Viggiano, D., Vallone, D., Ruocco, L.A., and Sadile, A.G. (2003).
Behavioural, pharmacological, morpho-functional molecular
studies reveal a hyperfunctioning mesocortical dopamine system
in an animal model of attention deficit and hyperactivity disorder.
Neurosci. Biobehav. Rev. 27, 683–689.
Wells, A.M., Janes, A.C., Liu, X., Deschepper, C.F., Kaufman, M.J.,
and Kantak, K.M. (2010). Medial temporal lobe functioning
and structure in the spontaneously hypertensive rat: comparison
with Wistar-Kyoto normotensive and Wistar-Kyoto hypertensive
strains. Hippocampus 20, 787–797.
Wilens, T.E., Klint, T., Adler, L., West, S., Wesnes, K., Graff, O., and
Mikkelsen, B. (2008). A randomized controlled trial of a novel
mixed monoamine reuptake inhibitor in adults with ADHD.
Behav. Brain Funct. 4, 24.
Wultz, B., Sagvolden, T., Moser, E.I., and Moser, M.B. (1990). The
spontaneously hypertensive rat as an animal model of attention-
deficit hyperactivity disorder: effects of methylphenidate on
exploratory behavior. Behav. Neural Biol. 53, 88–102.
Zeeuws, I. and Soetens, E. (2007). Verbal memory performance
improved via an acute administration of d-amphetamine. Hum.
Psychopharmacol. 22, 279–287.