Neurotransmitters

There are more than a dozen known or suspected neurotransmitters in the

brain. For psychopharmacologists, it is particularly important to know the
six key neurotransmitter systems targeted by psychotropic drugs:

1. serotonin
2. norepinephrine
3. dopamine
4. acetylcholine
5. glutamate
6. GABA (ã-aminobutyric acid)
Reuptake systems:

However, selective permeability of the membrane is required to allow

discharge as well as uptake of specific molecules, to respond to the needs
of cellular functioning. neurotransmitters, which are released from
neurons during neurotransmission and, in many cases, are also
transported back into presynaptic neurons as a recapture mechanism
following their release. This recapture – or reuptake – is done in order for
neurotransmitter to be reused in a subsequent neurotransmission. Also,
once inside the neuron, most neurotransmitters are transported again into
synaptic vesicles for storage, protection from metabolism, and immediate
use during a volley of future neurotransmission.

Both types of neurotransmitter transport – pre-synaptic reuptake as well

as vesicular storage – utilize a molecular transporter belonging to a
“superfamily” of twelve-transmembrane-region proteins. That is,
neurotransmitter transporters have in common the structure of going in
and out of the membrane 12 times. These transporters are a type of
receptor that binds to the neurotransmitter prior to transporting that
neurotransmitter across the membrane.
Criteria for a Neurotransmitter

1. The molecule is synthesized in the neuron.

2. The molecule is present in the pre-synaptic neuron and is released
on depolarization in physiologically significant amounts.
3. When administered exogenously as a drug, the exogenous
molecule mimics the effects of the endogenous neurotransmitter.
4. A mechanism in the neurons or the synaptic cleft acts to remove or
deactivate the neurotransmitter.
Neuromodulators
In contrast to the characteristically immediate and short-lived effects of a
neurotransmitter, causes either excitation or inhibition to the neuron.
o A neuromodulator, as the name implies, modulates the response of
a neuron to a neurotransmitter.
o The modulatory effect may be present for a longer time than is
usual for a neurotransmitter molecule to be present.
o Thus, a neuromodulating substance may have an effect on a neuron
over a long period of time,
o And that effect may be more involved with fine tuning than with
activating or directly inhibiting the generation of an action
potential.

Neurohormones
o A neurohormone is distinguished by the fact that it is released into
the bloodstream rather than into the extraneuronal space in the
brain.
o Once in the bloodstream, the neurohormone can then diffuse into
the extraneuronal space and have its effects on neurons.

Dopamine

CNS Dopaminergic Tracts

The three most important dopaminergic tracts for psychiatry are the

1. The nigrostriatal tract

Projects from its cell bodies in the substantia nigra to the corpus
striatum.
When the D2 receptors at the end of this tract are blocked by classic
antipsychotic drugs, parkinsonian side effects emerge.
In Parkinson's disease the nigrostriatal tract degenerates, resulting in the
motor symptoms of the disease.
Because of the significant association between Parkinson's disease and
depression, the nigrostriatal tract may somehow be involved with the
control of mood, in addition to its classic role in motor control.
D2 receptors in the caudate nucleus suppress the activity of the caudate
nucleus. The caudate neurons regulate motor acts by gating, in which
intended acts are actually carried out. The absence of D2 receptor activity
allows the caudate to dampen motor activity excessively, resulting in the
bradykinesia that typifies parkinsonism. At the other extreme, excess
dopamine activity in the caudate removes the gating control and may
result in extraneous motor acts, such as tics. A recent study of patients
with obsessive“compulsive disorder, for example, correlated increased
caudate dopamine analogue binding, which reflects increased numbers of
the D2 receptors, with more prominent clinical tics.

2. The mesolimbic-mesocortical tract

Projects from its cell bodies in the ventral tegmental area (VTA), which
lies adjacent to the substantia nigra, to most areas of the cerebral cortex,
and to the limbic system.
Because the tract projects to the limbic system and the neocortex, the
tract may be involved in mediating the antipsychotic effects of
antipsychotic drugs.

3. The tuberoinfundibular tract,

Projects from the arcuate nucleus and the periventricular area of the
hypothalamus, to the infundibulum and the anterior pituitary.
Dopamine acts as a release-inhibiting factor in the tract by inhibiting the
release of prolactin from the anterior pituitary.
Patients who take dopamine receptor antagonists often have roughly
threefold elevated prolactin levels because the blockade of dopamine
receptors in the tract eliminates the inhibitory effect of dopamine.

Dopamine Receptors
The five subtypes of dopamine receptors can be put into two groups.
1. In the first group, the D1 and D5 receptors stimulate the formulation
of cAMP by activating the stimulatory G protein, Gs.
The D5 receptor has only recently been discovered, and less is known
about it than about the D1 receptor.
One difference between these two receptors is that the D5 receptor has a
much higher affinity for dopamine than does the D1 receptor.

2. The second group of dopamine receptors is made up of the D2, D3,

and D4 receptors.
The D2 receptor inhibits the formation of cAMP by activating the
inhibitory G protein, Gi, and some data indicate that the D3 and D4
receptors act similarly.
One of the differences among the D2, D3, and D4 receptors is their
differential distribution.
The D2 receptor is prominent in the striatum (caudate nucleus and
putamen);
The D3 receptor is especially concentrated in the nucleus accumbens, in
addition to other regions;
The D4 receptor is especially concentrated in the frontal cortex, in
addition to other regions.
In a recent study, a scale of emotional detachment, with high values for
aloofness and vindictiveness and low values for overly nurturing behavior
and excessive exploitability, was used to rate 24 individuals, and then the
density of D2 receptors was determined in each person's putamen. A
strong correlation was found between high levels of detachment and a
low density of putaminal D2 receptors, whereas low levels of detachment
correlated strongly with high D2 receptor density. This finding is in
keeping with the clinical observation that D2 receptor antagonists (i.e.,
typical antipsychotic drugs) reduce the positive symptoms of
schizophrenia, such as hallucinations and delusions, but may worsen the
negative symptoms, such as social ambivalence and catatonia. In another
study, experts postulate that dopamine activity may act in the medial left
prefrontal cortex to suppress signals of emotional distress. A recent report
supporting this hypothesis correlated a genetic polymorphism in the D 4
receptor with differences in subjective reports of mood.

1 Monoamine Receptors: Overview

Primary
TransmitterSubtype Effector Proposed Clinical Relevance
Serotonin 5-HT1A ↓ AC Antidepressant action; partial agonist; anxiolytic
5-HT1B ↓ AC Possible role in locomotor activity, aggression
5-HT1D ↓ AC Target of antimigraine drug sumatriptan
5-HT1E ↓ AC Unknown
5-HT1F ↓ AC Target of antimigraine drug sumatriptan
5-HT2A ↑ PI Target of hallucinogens, atypical antipsychotics
turnover
5-HT2B ↑ PI Regulation of stomach contraction
turnover
5-HT2C ↑ PI Regulation of appetite, anxiety, seizures; target of
turnover hallucinogens, antipsychotics
5-HT3 Cation Antagonists antiemetic, anxiolytic, cognitive
selective enhancement
Ion channel
5-HT4 ↑ AC Modulation of cognition, anxiety
5-HTα Unknown Unknown
5-HTβ Unknown Unknown
5-HT6 ↑ AC Target of hallucinogens, atypical antipsychotics
5-HT7 ↑ AC Possible regulation of circadian rhythms
Histamine H1 ↑ PI Antagonists produce sedation, weight gain
turnover
H2 ↑ AC Antagonists for peptic ulcer disease
H3 Unknown Antagonists produce arousal, appetite suppression
Dopamine D1 ↑ AC D1 and D2 receptor stimulation synergistic;
required for stimulant effects of cocaine
 D2 ↓ AC Target of therapeutic and extrapyramidal effects
of dopamine receptor antagonists (“typical
antipsychotics―)
D3 ↓ AC Unknown
D4 ↓ AC Target of serotonin-dopamine antagonists
(“atypical antipsychotics―)
D5 ↑ AC Unknown
Adrenergic α1A,B,D↑ PI Antagonists antihypertensive
turnover
α2A,B,C ↓ AC Agonists sedative and antihypertensive
β1 ↑ AC Regulation of cardiac function
β2 ↑ AC Regulation of bronchial muscle contraction
β3 ↑ AC Regulation of adipose tissue function
Cholinergic M1 ↑ PI Regulation of cognition, seizures
turnover
M2 ↓ AC Regulation of cardiac function
M3 ↑ PI Regulation of smooth muscle contraction
turnover
M4 ↓ AC Target of antiparkinsonian anticholinergic drugs
M5 ↑ PI Unknown
turnover
NAChR Cation Regulation of tobacco use, seizures; possible
selective cognitive enhancement
Ion channel
↑ AC, increases activity of adenylate cyclase; ↓ AC, decreases activity of
adenylate cyclase; ↑ PI turnover, increases turnover of phosphoinositides.

Norepinephrine and Epinephrine

Although norepinephrine and epinephrine are discussed together,
norepinephrine is the more important and more abundant of the two
related neurotransmitters in the brain, although adrenally derived
epinephrine is more abundant than norepinephrine in the serum.
The norepinephrine system and the epinephrine system are also referred
to as the noradrenergic system and the adrenergic system, respectively.
The receptors are referred to simply as adrenergic receptors, however,
because they are receptors for both epinephrine and norepinephrine.

CNS Noradrenergic Tracts

The major concentration of noradrenergic (and adrenergic) cell bodies
that project upward in the brain is in the compact locus ceruleus in the
pons.
The axons of these neurons project through the medial forebrain bundle
to the cerebral cortex, the limbic system, the thalamus, and the
hypothalamus.
Noradrenergic and Adrenergic Receptors
The two broad groups of adrenergic and noradrenergic receptors, often
just referred to as adrenergic receptors, are
the α-adrenergic receptors and the β-adrenergic receptors.
The advances of molecular biology have now subtyped these receptors
into three types of α 1-receptors (α 1A, α 1B, and α 1D), three types of α 2-
receptors (α 2A, α 2B, α 2C), and
three types of β -receptors (β 1, β 2, and β 3).

Although the field is changing rapidly, all α1-receptors seem to be linked

to the phosphoinositol turnover system, α-receptors seem to inhibit the
formation of cAMP, and β-receptors seem to stimulate the formation of
cAMP. The surface availability and the efficiency of signal transduction
of the adrenergic receptors are constantly regulated by phosphorylations
and changes in protein–protein interactions. Significant data have long
been available on the β1- and β2-receptors, which regulate the function of
nearly every organ in the body, often in antagonism to the effects of the
α-receptors. The β3-receptors have recently been found to regulate
energy metabolism. They are expressed in adipocytes, and their activation
by agonists reduces the amount of body fat. They, therefore, are a target
for the development of antiobesity drugs.

Serotonin

CNS Serotonergic Tracts

The major site of serotonergic cell bodies is in the upper pons and the
midbrain”specifically, the median and dorsal raphe nuclei and, to a
lesser extent, the caudal locus ceruleus, the area postrema, and the
interpeduncular area.
These neurons project to the basal ganglia, the limbic system, and the
cerebral cortex.

Serotonergic Receptors
Seven types of serotonin receptors are now recognized: 5-HT1 through 5-
HT7, with numerous subtypes, totaling 14 distinct receptors.
The diversity of serotonin receptors has initiated a significant effort to
study the distribution of serotonin receptor subtypes in pathological states
and to design subtype-specific drugs that may be of particular therapeutic
benefit in specific conditions.
For example, buspirone (BuSpar), a clinically effective anxiolytic, is a
potent 5-HT1A agonist, and other 5-HT1A agonists are being developed
for the treatment of anxiety and depression.

Clozapine, the prototypical serotonin-dopamine antagonist antipsychotic

agent, has significant activity as an antagonist of 5-HT2 receptors, and
this observation has initiated a major effort to study the role of this
serotonin receptor subtype and to develop drugs that are 5-HT2
antagonists for the treatment of schizophrenia.

Antagonists of the 5-HT3 receptor are also under study as potential

antianxiety and antipsychotic compounds.

The distributed serotonin receptors are sometimes responsible for the side
effects of serotonergic drugs, many of which nonspecifically raise
serotonin levels and thus indiscriminately increase receptor activation.

Serotonin receptors in the basal ganglia may be responsible for akathisia

and agitation;

5-HT3 receptors in the brainstem vomiting center (area postrema) or the

hypothalamus may cause nausea and vomiting;

receptors in the limbic system may cause an initial increase in anxiety;

receptors in various parts of the brainstem sleep centers may produce
either insomnia or somnolence; spinal cord pathways may produce sexual
dysfunction; receptors in the intestines (where 90 percent of the body's
serotonin is found) may cause gastrointestinal upset and diarrhea; and
receptors in the cranial blood vessel may cause headache.

Which, if any, of these adverse effects will occur in a particular patient

cannot be predicted.

Histamine
Neurons that release histamine as their neurotransmitter are located in the
hypothalamus and project to the cerebral cortex, the limbic system, and
the thalamus.

Histamine receptors:
H1-receptor stimulation increases the production of IP3 and DAG;
H2 stimulation increases the production of cAMP; and the
H3 receptor may regulate vascular tone.
Blockade of H1 receptors is the mechanism of action for allergy
medications and is partly the mechanism for commonly observed side
effects (e.g., sedation, weight gain, and hypotension) of some
psychotropic drugs.

Acetylcholine

CNS Cholinergic Tracts

A group of cholinergic neurons in the nucleus basalis of Meynert
projects to the cerebral cortex and the limbic system.
Additional cholinergic neurons in the reticular system project to the
cerebral cortex, the limbic system, the hypothalamus, and the thalamus.

Some patients with dementia of the Alzheimer's type or Down syndrome

appear to have specific degeneration of the neurons in the nucleus basalis
of Meynert.

Cholinergic Receptors
The two major subtypes of cholinergic receptors are muscarinic and
nicotinic.
There are five recognized types of muscarinic receptors with various
effects on phosphoinositol turnover, cAMP and cGMP production, and
potassium ion channel activity.
Muscarinic receptors are antagonized by atropine and by the
anticholinergic drugs.
The nicotinic receptors are ligand-gated ion channels that have the
receptor site directly on the ion channel itself.
The nicotinic receptor is actually made up of four subunits (α, β, γ, and
δ). Nicotinic receptors can vary in the number of each of those subunits;
thus, a multitude of subtypes of nicotinic receptors exist, based on the
specific configuration of the subunits.

Selected Neuropeptide Transmitters

Adrenocorticotropin hormone (ACTH)
Angiotensin
Atrial natriuretic peptide
Bombesin
Calcitonin
Calcitonin gene-related peptide (CGRP)
Cholecystokinin (CCK)
Cocaine and amphetamine regulated transcript (CART)
Corticotropin-releasing factor (CRF)
Dynorphin
β-Endorphin
Leu-enkephalin
Met-enkephalin
Galanin
Gastrin
Gonadotropin-releasing hormone (GnRH)
Growth hormone
Growth hormone-releasing hormone (GHRH; GRF)
Insulin
Motilin
Neuropeptide Y (NPY)
Neuromedin N
Neurotensin (NT)
Orexin
Orphanin FQ/Nociceptin
Oxytocin (OT)
Pancreatic polypeptide
Prolactin
Secretin
Somatostatin (SS; SRIF)
Substance K
Substance P
Thyrotropin-releasing hormone (TRH)
Urocortin
Vasoactive intestinal polypeptide (VIP)
Vasopressin (AVP; ADH)

γ-Aminobutyric Acid (GABA)

GABA is found almost exclusively in the CNS, and it does not cross the
blood-brain barrier.
The highest concentrations are in the midbrain and diencephalon, with
lower amounts in the cerebral hemispheres, the pons, and the medulla.
GABA is synthesized from glutamate by the rate-limiting enzyme
glutamic acid decarboxylase (GAD), which requires pyridoxine (vitamin
B6) as a cofactor. GABA is the primary neurotransmitter in intrinsic
neurons that function as local mediators for the inhibitory feedback loops.
GABA commonly coexists with biogenic amine neurotransmitters,
glycine, and peptide neurotransmitters, including somatostatin, NPY,
CCK, substance P, and vasoactive intestinal peptide (VIP).
Because GABA is thought to suppress seizure activity, anxiety, and
mania, considerable effort has been devoted to synthesizing drugs that
potentiate GABA activity. One such drug, progabide, is a hydrophobic
GABA receptor agonist with good brain penetration, which has
anticonvulsant activity. Tiagabine (Gabitril), which inhibits the GABA
transporter, and vigabatrin (Sabril), which inhibits GABA-T, raise the
effective synaptic levels of GABA and exhibit anticonvulsant activity.
The anticonvulsant topiramate (Topamax) potentiates GABA receptor
activity by unclear mechanisms. Gabapentin (Neurontin), a GABA
derivative, is an effective anticonvulsant with good brain penetration; yet,
curiously, it has no activity at GABA receptors or the GABA transporter.
The GABA receptor has binding sites for the benzodiazepines, and the
barbiturates. The benzodiazepines increase the affinity of the A-receptor
for GABA. The β-carbolines are a class of drugs that are inverse agonists
of the benzodiazepine receptors; thus, their activity results in anxiety and
convulsions. Flumazenil (Romazicon) is a benzodiazepine antagonist that
is currently being used in hospital emergency rooms as a treatment for
benzodiazepine overdose.

Glycine
Glycine is synthesized primarily from serine by the actions of serine
trans-hydroxymethylase and β-glycerate dehydrogenase, both of which
are rate limiting.
Glycine does double duty as a mandatory adjunctive neurotransmitter for
glutamate activity and an independent inhibitory neurotransmitter at its
own receptors. The excitatory amino acid-binding site for glycine on the
NMDA glutamate receptor is referred to as the non“strychnine-sensitive
glycine receptor, and it contrasts with the strychnine-sensitive glycine
receptor, which is an inhibitory receptor. Improvement of NMDA
receptor activity by occupancy of the glycine-binding site has been
hypothesized to present an adjunctive mode for the treatment of
schizophrenia. Some, but not all, clinical trials of this hypothesis have
shown a reduction in the negative symptoms of schizophrenia by glycine.

Glutamate
Glutamate is synthesized from glucose and glutamine in presynaptic
neuron terminals and is stored in synaptic vesicles. Once released into the
synaptic cleft, it acts on receptors, and its action is terminated by highly
efficient uptake into the presynaptic neuron or adjacent glia.
Glutamate is the primary neurotransmitter in cerebellar granule cells, the
striatum, the cells of the hippocampal molecular layer and entorhinal
cortex, the pyramidal cells of the cortex, and the thalamocortical and
corticostriatal projections.
Glutamate release is stimulated by nicotine.
Of the five major types of glutamate receptors, the NMDA receptor is the
best understood and most complex of the receptors, because it may play
an essential role in learning and memory, as well as psychopathology.