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Neurotransmitters in the

Nervous System:

Catecholamines

Neuroanatomical location
Synthesis and break-down
Behavioral and physiological function
Central neurotransmitter systems and
behavior

 Remember that transmitter receptors can be pre-


synaptic or post-synaptic.
 When pre-synaptically located on the axon terminal,
they modulate release by changing the amount of
Ca+ influx (decrease or increase); activation of
autoreceptors on the soma or dendrites changes the
amount of firing.
 Postsynaptic receptors can be ionotropic or
metabatropic. The latter work via G proteins,
second messenger systems and kinases.
Take note…
 As we study the various
neurotransmitter systems, note:
 Some cell bodies are compactly
arranged in cell nuclei within the brain,
whereas others are more spread out.
 Some project in more or less discrete
tracts, whereas others have a
widespread projection.
Similarities and differences
 Are there similar synthetic or metabolic pathways?
 How do the transmitters get packaged into synaptic
vesicles?
 How do transmitter molecules get removed from the
synapse? Is there a role for glial cells? (e.g., astroglia)
 Do they induce excitatory or inhibitory effects on their post-
syaptic targets?
 Do they synapse on ionotropic or metabotropic post-
synaptic receptors?
 What are the various types of receptors that are activated
by the neurotransmitter and how do they differ? (e.g.,
location, subunits, binding by different drugs, etc.)
What are the ligands that activate these
neurotransmitter receptors?

 Interestingly, many come from plants or


animals

 This suggests that they developed in


response to the organism’s interaction
with its environment thru evolution
Catecholamines:
Norepinephrine and Dopamine
 Also includes epinephrine in the
neuroendocrine system (adrenaline)
 Core structure of catechol and a
nitrogen-containing group called an
amine
 Also called “monoamines” or biogenic
amines = transmitters that contain one
amine group (this group includes
serotonin, 5-HT, which is not a
catecholamine)
Common synthetic pathway for dopamine and norepinephrine

Catecholamines are
synthesized from the
precursor tyrosine, an
amino acid obtained
from dietary sources.
TH is the enzyme that
acts as a catalystDOPA
DOPA is a precursor for
dopamine. L-DOPA is
used to treat Parkinson’s
Disease, so this is the
mechanism of action for
this treatment drug.
Common synthetic pathway for dopamine and norepinephrine

An additional
synthetic step
converts DA to
NE.
The enzyme
DBH catalyzes
this reaction.
TH is the rate
limiting enzyme
for CA
synthesis.
Interfering with the synthesis of dopamine and norepinephrine

In research, alpha-
para-methyl-tyrosine
blocks TH, blocking
all CA synthesis.

In humans, it
produces signs of
clinical depression,
suggesting that CAs
are involved in the
transmitter
abnormalities that
produce symptoms
of depression.
Other mechanisms of action – Drug effects on CAs

Amphetamine and
methamphetamine cause
release of CAs from the
neuron.
They stimulate behavior in
low doses and produce
focused stereotypy in high
doses.
In humans, they produce
increased alertness,
heightened energy, euphoria,
insomnia and other
behavioral activation.
Interfering with CA “packaging” and reuptake into neurons

Reserpine, from the plant


Rauwolfia Serpentina,
interferes with CA packaging
into vesicles. Blocks the
vMAT2

Unpackaged, CAs are


broken down inside of
the cell (thus, not
released), also producing
depressive symptoms.
Behavioral depression produced by reserpine
Single-
Catecholamine Release spiking
mode: cell
generates
action
 Determined by rate of cell firing potentials that
 Single spike (Tonic release) appear at
irregular
 Burst release (Phasic release) intervals (tonic
release of
DA).
Burst mode:
involves trains
of 2 to 20
spikes at a
higher
frequency
(phasic
release of
DA).
Catecholamine inactivation
 CAs are inactivated by 2 mechanisms:
 reuptake into the neuron by the DA transporter and NE
transporter (DAT and NET)
 CAs can be broken down in the cell and in the synapse by
two enzymes: COMT and MAO
 MAO inhibitors are used as antidepressants; tricyclic
antidepressants inhibit the NET
 The psychostimulants cocaine and amphetamine also
inhibit NET and DAT (recall that amphet also stimulates
release)
 Ritalin, a psychostimulant used to treat ADHD, blocks the
CA reuptake transporters as well
Interfering with CA reuptake into neurons

Cocaine, Ritalin and


tricyclic antidepressants
are CA reuptake blockers

When the reuptake mechanism is


blocked, more CAs remain in the
synapse to activate receptors, so
the net effect is increasing
neurotransmitters (i.e., Indirect
Agonists)
CA Metabolites
 When DA is broken down metabolites are
produced
 These can be measured in plasma, CSF, in
vivo dialysates, or in post-mortem brain
homogenates to determine how much
dopaminergic activation there is/was
 These are techniques we can use to measure
brain chemistry (e.g., after amphetamine
administration in a rat, in post-mortem
studies of suicide victims, etc)
Dopaminergic Systems
 Participate in (1) complex motor functions via the Basal
Ganglia, (2) mood and emotion via subcortical structures
in the limbic system, and (3) cognition (a cognitive-
emotion interface) in the frontal cortex

 But it is difficult to separate these psychological processes

 For example, consider “Paradoxical Kinesia” in PD, and the


importance of both sensory cues and motivation in a
dopaminergic motor system typically considered important
for JUST movement!
Figure 5.5 A typical
dopaminergic neuron
Where are
MAO and
COMT?

What do
autoreceptors
do? Think of
dopamine
“thermostats”
…When there
is a lot of
dopamine in
the synapse,
they
DECREASE
further
release.
Autoreceptors

 Catecholamine release is inhibited by


autoreceptors on neuron cell bodies,
terminals, and dendrites.
 The autoreceptors enhance the opening
voltage-gated K+ channels.
 This shortens the duration of action
potentials and reduces Ca2+ influx and,
thus, vesicle exocytosis.
DA cells of origin

 Cell bodies for DA projection systems are


found in the midbrain

 Two collections of neurons include the


Substantia Nigra and the Ventral Tegmental
Area (A9 and A10)

 Both have discrete projections


Three ascending dopaminergic
projection systems
Organization and Function of the
Dopaminergic System

One SN projection A9
Two VTA projections A10
The nigrostriatal dopaminergic system

The caudate+putamen (striatum) and GP are nuclei in the Basal Ganglia


DA neurons in the substantia nigra degenerate in Parkinson’s disease
Parkinson’s Disease—A “Radical” Death of Dopaminergic Neurons?

Normal SN neurons in the primate appear dark due to the accumulation of the pigment
neuromelanin. These cells are lost over normal human aging, but show accelerated
degeneration in PD.
The nigrostriatal DA system
 A “resilient” brain neurotransmitter system:
Parkinson’s symptoms are not seen until
approximately 80% of DA is depleted from this
nigrostriatal system because remaining neurons
show compensatory increases in release!
 Selective destruction of DA neurons from the
substantia nigra can be induced by infusion of the
neurotoxin, 6-hydroxydopamine (6-OHDA) which
is taken up by the CA transport proteins, into the
cell
Damage to the nigrostriatal pathway on one side of the brain

Selective depletion of dopamine in the nigrostriatal track of the rat can be


induced by direct infusion of the neurotoxin 6-hydroxydopamine
The mesolimbic DA projection system: Drug abuse and central “reward”

The nucleus accumbens is a subcortical structure


that is included in the brain’s limbic system

This mesolimbic system is involved in motivation, goal


directed behavior and central processes of reward
(salience, prediction and expectation); all drugs of
abuse activate this system.
The mesocortical DA system: Drug abuse and central “reward” con’t…

Includes projections to the frontal cortex that are involved in “working


memory” (via D1 receptors) and may be involved in cognitive deficits
seen in schizophrenia.
FC has a role in emotion as well
VTA Projections
 Together, these two projection systems
from the VTA are called the
mesocorticolimbic or corticomesolimbic
DA system
 They both seem to be involved in the
brain pathology of schizophrenia
 In fact, cortical DA areas regulate DA in
the nucleus accumbens
D1 and D2 metabotropic receptor families: D1 through D5
Organization and Function of the
Dopaminergic System

 DA has five receptor subtypes, D1 to D5.


 All are metabotropic: They interact with G

proteins and function via second


messengers.
 Two Families: D1 and D2

 D1 and D5 are similar (D1-like receptors).

 D2, D3, and D4 are a also similar (D2-like


receptors).
Organization and Function of the
Dopaminergic System

 D2 receptors function as autoreceptors and


as postsynaptic receptors.
 Nearly all current anti-schizophrenic drugs

are D2 receptor antagonists.


 D1 receptor activation stimulates adenylyl

cyclase and synthesis of cAMP; D2 receptor


activation has the opposite effect.
D2 Autoreceptors control DA release

Dopamine D2
receptors are
located on pre-
synaptic terminals
and also are post-
synaptically located
They are the target
of early anti-
schizophrenic drugs If DA receptors are continuously blocked by
an antagonist, these DA receptors develop
up-regulation (increase in number or
strength)
Organization and Function of the
Dopaminergic System

 Apomorphine: An agonist that stimulates


both D1 and D2 receptors.
 Causes behavioral activation similar to
that seen with stimulants like cocaine and
amphetamine.
Organization and Function of the
Dopaminergic System

 Receptor-selective agonists and


antagonists help us understand which
behaviors are under the control of a
particular receptor subtype.
 SKF 38393 is an agonist for D1 receptors;
quinpirole activates D2 and D3 receptors.
Organization and Function of the
Dopaminergic System

 DA receptor antagonists suppress


exploratory and locomotor behavior.
 At higher doses, such drugs can result in

catalepsy—lack of spontaneous
movement.
 Usually associated with D2 receptor
blockers such as haloperidol, but also D1
blockers such as SCH 23390.
Figure 5.13
Organization and Function of the
Dopaminergic System

 DA receptor agonists and antagonists have


provided much information about the
behavioral functions of DA.
 A newer approach: Manipulate genes for
individual components of the dopaminergic
system and determine the behavioral
consequences.
Organization and Function of the
Dopaminergic System

 The dopaminergic system is one of the


most intensively studied neurotransmitter
systems using genetic engineering
approaches.
 Each gene knockout produces a unique

behavioral phenotype, compared to wild-


type animals.
Organization and Function of the
Dopaminergic System

 DA transporter knockout mice are


extremely hyperactive; DA can’t be
removed from the extracellular fluid.
 The mice also have cognitive deficits and
impulsivity, traits often seen in children
with ADHD.
Box 5.2 The Cutting Edge:

Using Molecular
Genetics to
Study the
Dopaminergic
System
(Part 1)
Organization and Function of the
Dopaminergic System
 DA receptor knockout mice:
 D1 receptor knockout mice exhibit
behavioral abnormalities and deficits in
several kinds of cognitive tasks.
 D2 knockout mice show impairment in

spontaneous movement, coordination, and


posture control.
 D1 and D2 double knockouts die in the
second or third week of life.
Organization and Function of the
Dopaminergic System

 DA knockout mice are used to study


reactions to psychoactive drugs.
 DA transporter and D1 or D2 receptor
knockout mice show reduced or no
increase in locomotion after treatment with
psychostimulants, such as cocaine.
 D4 receptor knockout mice are hyper-

sensitive to methamphetamine and


cocaine.
Box 5.2 The Cutting Edge: Using
Molecular Genetics to Study the
Dopaminergic System (Part 2)
Organization and Function of the
Dopaminergic System

 If a D2 receptor antagonist, such as


haloperidol, is given to rats on a long-term
basis, the rats develop behavioral
supersensitivity.
 If the treatment is stopped and an
agonist, such as apomorphine, is given,
these rats respond more strongly than
control subjects.
Organization and Function of the
Dopaminergic System

 This behavioral supersensitivity may be


due to increased density of D2 receptors on
postsynaptic cells in the striatum
(receptor up-regulation).
 Lack of normal neurotransmitter input

causes the neurons to increase their


sensitivity by making more receptors.
Noradrenergic Systems
 Important role in regulating “behavioral
state”
 From general arousal to very focused
attention and vigilance (sustained attention)
 These functions fall along a continuum
from:
 Regulation of sensory processing
 To attention
 And finally, storing information into memory
Noradrenergic functions, con’t

 Also important for behaviors regulated


by the hypothalamus – sleep, eating,
sexual behavior, etc.
 Involved in the ANS – sympathetic
activation
Cells of origin
 All norepinephrine containing cells are located
in the Locus Coeruleus in the brain stem

 Widespread innervation of the forebrain,


including the cortex, limbic system and
hypothalamus (“highly divergent”, unlike
discrete tracts in the DA system)

 There are also descending pathways thru the


spinal cord where NE is important in the ANS
– sympathetic nervous system
Ascending and descending projections from the locus coeruleus
The NE system
innervates many brain
areas and structures,
including the cortex
(“widespread”)
Brain NE is involved in behavioral arousal or “alerting”…

Neurons in the LC show


tonic activity in
electrophysiological
recording, during
behavioral arousal/alerting
Similarly…
 In monkeys and rodents, focused
attention on a task is seen with
moderate levels of tonic activation in
the LC
 High tonic activity in the LC is needed
for “scanning, labile attention” and
focused attention is impaired
 Role in ADHD?
Rats showed increased time awake after adrenergic
agonists (to “turn on” NE brain systems)
Noradrenergic receptors
 NE receptors include alpha and beta
 All are metabatropic and work thru G protein
coupling (ie., second messenger systems)
 They can be pre- or post-synaptically located
 Recall that activation of pre-synaptic
receptors – autoreceptors – reduces the
amount of neurotransmitter released from the
neuron
 Thus, drugs that bind to NE receptors will
bind at both pre-synaptic and post-synaptic
receptor sites (recall, will produce opposite
effects on neural activation)
Effect of norepinephrine on eating behavior

When NE is infused into the


PVN (periventricular nucleus
of the hypothalamus), rats
are stimulated to eat, even
if they are sated (full). This
effect is due to activation of
alpha receptors.
Organization and Function of the
Noradrenergic System

 Peripheral component
 Many neurons in the sympathetic nervous
system use NE as the transmitter. Their
fibers extend to target organs throughout
the body from both the brain, and the
adrenal gland.
Organization and Function of the
Noradrenergic System

 NE can reach an organ such as the heart in


two ways:
 It can be released from sympathetic
noradrenergic neurons at synapse-like
contacts with cardiac cells.
 It can be released from the adrenal
glands and travel in the bloodstream to the
heart (but cannot cross the blood-brain
barrier).
Organization and Function of the
Noradrenergic System

 Blood-borne NE and EPI work together


with NE released as a transmitter from
sympathetic nerves to mediate the
physiological changes that make up the
“fight-or-flight” response:
 Effects include elevated blood pressure
and heart rate, decreased digestive
activity, dilation of blood vessels to skeletal
muscles, heart and brain.
Organization and Function of the
Noradrenergic System

 Adrenergic receptors (adrenoceptors) are


metabotropic. Two subtypes: α and β.
 α2-receptors reduce synthesis of cAMP (like

D2 receptors).
 α1-receptors operate via phosphoinositide

second-messenger system.
 β1- and β2-adrenoceptors stimulate

adenylyl cyclase and enhance synthesis of


cAMP (like D1 receptors).
Organization and Function of the
Noradrenergic System

 The central noradrenergic system is


involved in many behavioral functions.
 Focus here is on its role in arousal,

cognition, and consolidation of memories


of emotional experiences.
Organization and Function of the
Noradrenergic System

 LC neurons fire more rapidly during waking


than during sleep.
 Noradrenergic pathways from the LC to the
medial septal and medial preoptic areas
are involved in wakefulness.
 Experiment: α1-receptor agonist
phenylephrine and/or general β-receptor
agonist isoproterenol were injected into
the medial septal area of rats.
Rats showed increased time awake after adrenergic
agonists (to “turn on” NE brain systems)

Phenylephrine: alpha1 agonist, isoproterenol: Beta agonist


Figure 5.16 Wakefulness-promoting effects of
adrenergic agonists infused into the lateral
hypothalamic area
Organization and Function of the
Noradrenergic System

 LC also projects to prefrontal cortex (PFC),


which has roles in cognitive functions like
attention and working memory.
 Activation of α2-receptors in the PFC using
selective agonists, such as clonidine and
guanfacine, enhances working memory.
Figure 5.17 Guanfacine facilitation of working memory
in aged monkeys (alpha-2 agonist)
Organization and Function of the
Noradrenergic System

 Activation of α1-receptors in the PFC has a


deleterious effect on cognitive functions.
 NE has a lower affinity for α1-receptors
than for the α2-receptor subtype found in
high levels in the PFC.
 NE facilitates PFC function and cognitive
tasks under normal conditions by activating
α2-adrenoceptors there.
Organization and Function of the
Noradrenergic System

 Increased NE associated with stress


increases α1-receptor activation, which can
lead to cognitive impairment.
 The hypothesis predicts that cognitive
functions, such as working memory
function, are optimized at intermediate
levels of PFC noradrenergic activity.
Figure 5.18 Modulation of working memory by adrenergic receptor
subtypes in the prefrontal cortex
Organization and Function of the
Noradrenergic System

 Evidence from animal studies indicates that


NE, EPI, and glucocorticoid hormones
modulate the consolidation of emotional
memories.
 One-trial passive avoidance learning
paradigm is commonly used to evaluate
memory consolidation.
Figure 5.19 Memory
enhancement by
epinephrine and glucose
using a one-trial passive
avoidance learning
paradigm (Part 1)
Organization and Function of the
Noradrenergic System

 Stress associated with one-trial passive


avoidance learning produces increased EPI
and glucocorticoid secretion from the
adrenal glands.
 Central noradrenergic neurons also
increase NE release in the brain.
 All of these processes are believed to play

some role in passive avoidance memory


consolidation.
Organization and Function of the
Noradrenergic System

 The memory-enhancing effects of EPI may


be mediated by its ability to increase blood
glucose levels.
 Epinephrine has undesirable side effects,
which diminishes its usefulness as a
potential cognitive enhancer, but glucose
or a drug that boosts blood glucose levels
might be effective.
Organization and Function of
the Noradrenergic System

Figure 5.19
Memory
enhancement by
epinephrine and
glucose using a
one-trial passive
avoidance
learning paradigm
(Part 2)
Organization and Function of the
Noradrenergic System

 Adrenergic agonists or antagonists are


often used in treatment of non-psychiatric
conditions because of the widespread
distribution of adrenergic receptors in
peripheral organs.
 Agonists that activate both α- and β-

receptors are used to treat bronchial


asthma, but there are undesirable side
effects.
Organization and Function of the
Noradrenergic System

 Asthma is more commonly treated with a


selective β2-agonist, such as albuterol
(Ventolin), in an inhaler.
 Beta-receptors in the airways are β2
subtype; the heart has mainly β1 subtype.
Albuterol alleviates bronchial congestion
without producing adverse cardiovascular
effects.
Organization and Function of the
Noradrenergic System

 Cold medications are also based on properties of


peripheral adrenergic receptors. Phenylephrine
(decongestant) is an α1-receptor agonist (also
Sudafed or pseudoephedrine)

 α2-receptor agonists, such as clonidine, are often


used to treat hypertension. They inhibit activity
of the sympathetic nervous system while
stimulating the parasympathetic system.
Organization and Function of the
Noradrenergic System

 The α1-antagonist prazosin (Minipress)


and the general β-antagonist propranolol
(Inderal) are used to treat hypertension.
 Prazosin blocks α1-receptors that cause
blood vessel constriction; propranolol
blocks β-receptors in the heart, reducing
its contractile force.
Organization and Function of the
Noradrenergic System

 β1 is the main subtype in the heart; β1-


selective antagonists, such as metoprolol
(Lopressor), have fewer side effects.
 β-antagonists (beta blockers) are also used
to treat generalized anxiety disorder. They
reduce the physical symptoms, such as
palpitations, flushing, and tachycardia
(racing heart).