سلوكية 1

Chapter 1
Behavioral
Neurochemistry
Dr. Mohamed Abu-Alsebah
General-, Forensic- & Neuro-
Psychiatrist
Community Mental Health Specialist
Director of Mh Services, MoH

I. Introduction: Complexities in the
Neurochemistry of Behavioral Disorders
 Certain chemical substances may influence
mood, thought, and action.
 With the discovery of neuroleptics,
antidepressants, lithium, L-dopa, LSD, and
other drugs that have a profound effect on
normal and abnormal behavior, the field of
psychopharmacology has grown
considerably and, with it, interest in the
basic biochemistry of behavior.

A. Neurotransmitter disturbances
Many behavioral disorders – particularly
psychiatric and movement disorders – are
associated with disturbances of specific
neurotransmitters.
1. Although schizophrenia, tardive dyskinesia, and
Parkinson’s disease are associated with
dopaminergic abnormalities, and depression
with dysfunction in norepinephrine pathways,
many neurochemical abnormalities are proposed
for each of these conditions.
2. Response to drugs is a complex issue i.e., very
few psychopharmacologic drugs affect a single
transmitter system.

B. Underlying pathology
All behavioral abnormalities represent:
 The primary pathologic process
 Brain’s attempt to correct or compensate for it.

Conditions involving only a limited number of
neurochemical systems usually demonstrate
changes in other neurochemical systems.
C. Other factors that influence a patient’s
neurochemical status include age, gender, diet,
and pharmacotherapy – all of which affect
behavior.

II. Neuronal Transmission of Information
Roman y Cajal: “neuron doctrine” The
neuron is the basic unit of the nervous system.
Information basic to behavior is transferred, in
the form of specific chemicals and energy, both
within neurons and between neurons.
A. Neuronal membranes
Neuronal membranes play an important role in
both intra-neuronal and inter-neuronal processes.
They contain the means by which information is
transferred from one neuron to the next.
Information transfer across neurons occurs via
electrical or chemical changes.

1. Ion channels
The electrical means of neuronal transfer involves
the action potential: When a neuron is
stimulated, a dramatic change in the electrical
potential across the axonal membrane is
propagated down the length of the axon.
a. The action potential depends on the opening
and closing of ion channels that allow the
passage of ions such as Na, K, Cl, and Ca.
b. The passage of these ions across the neuronal
membrane causes depolarization (in which the
electrical potential differences across the
membrane rises from approximately -70 mV to
-15 mV), followed by repolarization (the
baseline high potential differences is restored).

2. Receptors
The chemical means of information transfer
across neurons involves neurochemical
receptors located in the membrane itself.
a. Neurochemical receptors are proteins that
bind to specific chemical substances, which
results in the eventual triggering of specific
processes within the neuron.
b. These receptors are important for the action
of neurotransmitters, neuromodulators,
and neurohormones.

B. Intra-neuronal transport
Information – in the form of specific
chemical substances – can pass through the
body of a neuron from one portion to
another, often along axons or dendrites,
and can influence some specific aspect of
neuronal function (e.g., nuclear processes,
energy metabolism).
 Cyclic nucleotides, calcium, and
phosphatidyl-inositol are important
intra-neuronal “messengers”.

1. Cyclic nucleotides are substances such as
cAMP and cGMP.
 They are called second messengers because
they help translate the information received from
extracellular messengers (e.g., neurotransmitters,
hormones) into an intracellular response.
 Not all neurotransmitters exert their effects
through the cyclic nucleotide system.
a. Certain neurotransmitters – by binding to
receptors – activate adenylate cyclase, the
enzyme that catalyses the formation of cAMP
from ATP.

The increase in cAMP concentration may
then activate cAMP-dependent protein
phosphorylation, causing a change in ion
permeability in the neuronal membrane.
b. Some receptors (possibly including α2-
adrenergic receptors, dopamine D2
receptors, somatostatin receptors, certain
muscarinic cholinergic receptors and
opiate receptors) inhibit, rather than
activate, adenylate cyclase.

c. The regulation of adenylate cyclase occurs
through guanine-nucleotide binding proteins,
G proteins.
Gs proteins stimulate and Gi proteins inhibit
adenylate cyclase; the exact function of Go
proteins is less clear.
2. Calcium and several associated binding
proteins – most notably calmodulin – form
another second messenger system.
a. Depolarization is associated with significant
quantities of calcium entering the neuron.

b. The calcium binds with calmodulin, to associate
with and modulate a number of calcium-
dependent enzymes, such as a calcium-
calmodulin-dependent protein kinase, certain
types of adenylate cyclase, phosphodiesterase,
and ATPase.
3. Phosphatidyl-inositol is a membrane
phospholipid that is hydrolyzed by a specific
phospholipase C following receptor occupation to
yield diacylglycerol (DAG) and inositol
triphosphate, which in turn activate protein kinase
C and increase intracellular calcium, respectively.

C. Inter-neuronal transport
1. Synapse = connection, the synapses are the
primary facilitators of the inter-neuronal transfer
of information.
Three synapses : chemical, electrical, and conjoint.
a. Chemical synapses: the most important type.
Each consists of a specific region where the
membranes of two neurons are in close
approximation.
A chemical messenger released from the pre-
synaptic membrane travels across the synaptic
cleft and acts on a specific receptor on the
postsynaptic membrane.

In some cases the messenger act on
receptors, known as auto-receptors,
on the presynaptic membrane.
b. Electrical synapses, transmit
information directly through the
transfer of an electrical charge and do
not employ chemical messengers.
c. Conjoint synapses operate through
both chemical and electrical means.

2. Neuroregulators are chemicals that carry
information between neurons.
They include neurotransmitters,
neuromodulators, and neurohormones.
 Neurotransmitters are neuroregulators
that exert their effects on specific pre- or
postsynaptic receptors.
The transfer of information by
neurotransmitters takes 1 to 2 m.sec, in
contrast to that mediated by other
neuroregulators, which takes much longer.

b. Neuromodulators, released from presynaptic
membranes and exert their effects on receptors.
Neuromodulators are released from membranes
other than synaptic ones, and they may act on
receptors located on large numbers of neurons.
Their effects last longer than those of
neurotransmitters on certain synapses.
c. Neurohormones also act on receptors located
on neurons and are released into the systemic
circulation and, thus, travel throughout the body,
unlike the other neuroregulators.

3. Types of neurotransmitters
a. They are divided into two types, depending on
their effects on the postsynaptic neuron.
(1) Excitatory neurotransmitters increase the
firing of the postsynaptic neuron.
(2) Inhibitory neurotransmitters decrease the
firing of the postsynaptic neuron.
b. Some neurotransmitters are solely excitatory
(e.g., glutamate, aspartate) or solely inhibitory
(e.g., GABA, glycine), others may function
either way (e.g., dopamine, acetylcholine).
c. Some transmitters are excitatory or inhibitory at
different synapses on the same neuron.

4. Neurotransmitter criteria
a. Criteria to be considered a
neurotransmitter.
(1) It must be present in nerve terminals.
(2) Stimulation of the nerve must cause the
release of the transmitter in sufficient
amounts to exert its actions on the
postsynaptic neuron.
(3) The effects of the transmitter on the
postsynaptic membrane must be similar to
those of transmitter stimulation of the
presynaptic nerve, such as activating the
same ion channels.

(4) Pharmacologic agents should
alter the dose-response curve of the
applied neurotransmitter in the
same magnitude and direction that
they alter the naturally occurring
synaptic potential.
(5) A mechanism for inactivation or
metabolism of the transmitter must
exist in the vicinity of the synapse.

b. Classification
(1) Neurotransmitters that meet all of the criteria are
considered definite neurotransmitters and include
ACh, dopamine, norepinephrine, epinephrine,
GABA, serotonin, and glycine.
(2) Those that meet some, but not all, of the criteria
are considered supposed neurotransmitters and
include glutamate, aspartate, and substance P.
(3) Those that meet only one or two criteria are
considered neurotransmitter candidates and
include adenosine, cAMP, prostaglandins, and most
peptides.

5. Steps in neurochemical transmission
a. Synthesis
May occur either near the presynaptic membrane
where it is to be released or elsewhere in the
neuron.
Peptide neurotransmitters are synthesized in the
soma of the neuron and transported along the
axon to the nerve terminals.
b. Transport
It is moved from the site of its synthesis to the site
of its storage or release.
c. Storage
Often occurs in vesicles specific to that purpose.

d. Release
(1) For some neuroregulators, a vesicle
containing the regulator liberates its contents.
The regulator may simply diffuses out of both
the vesicle and the neuron or the vesicle
combines with the neuron plasma membrane,
externalizing its contents through the process
of exocytosis.
(2) The process of release is dependent on the
influx of calcium that occurs with
depolarization of the pre-synaptic membrane.
(3) Autoreceptors on the presynaptic neuron can
modulate the release of that transmitter.

e. Termination
The action of a neuroregulator may be terminated
by diffusion out of the receptor area,
metabolism of the regulator, or reuptake of the
regulator, usually into the presynaptic neuron.
Reuptake is the most important process for
monoamines, whereas metabolism is important
for ACh and the peptides.
6. Mechanism of neuro-regulator effects
a. Binding
Binding to the recognition site of specific
receptors is the first step in the action of
neurotransmitters.

b. Transduction
It is the process by which regulator binding with the
receptor results in a biologic response of the neuron.
(1) Transduction occurs through so-called effector
proteins, which are closely linked to the receptor
protein.
The basic types of effector proteins include nucleotide
cyclases that catalyze the formation of cyclic
nucleotides and ion channels that control passage of
certain ions through the membrane.
(2) Modulator proteins may be interposed between
the receptor and effector proteins and may
themselves have binding sites for neuromodulators
and neurohormones.

Modulator proteins, such as G proteins,
may provide the means through which
neuromodulators and neurohormones
affect synaptic function.
(a) Some neuromodulators, usually
peptides, coexist with neurotransmitters
in the same neuron and may regulate the
time course and the magnitude of the
postsynaptic activity of the
neurotransmitter.

(b) It was thought at one time that one neuron
could possess only one neuroregulator, which
had the same function (excitation or inhibition)
at every synapse of that neuron. This was
referred to as Dale’s principle, but it is now
known to be incorrect.
c. Amplification
Following transduction, the full response of the
neuron to the neurotransmitter occurs through
amplification of the initial response, which
may occur through the activation of enzymes,
proteins phosphorylation, hormone release, or
other mechanisms.

7. Neurochemical methods
There are two basic ways to study the interaction
between neurotransmitters, hormones, or drugs
and receptors:
Measurement of the biologic response of an
isolated organ preparation and measurement of
ligand binding to tissue slices or homogenates.
The ligand can be one of many agonists or
antagonists that bind to a certain receptor.
a. Identifying supposed receptors
(1) Ideally, putative receptors are identified by
receptor saturability, specificity, and
reversibility.

(a) Specific binding of a ligand is
characterized by high affinity and low
capacity.
(b) Nonspecific binding is characterized by
low affinity and high capacity.
(c) Binding of ligand to receptor should be
reversible.
(2) Much can be learned about receptors using
radioactive ligands, or radioligands.
The number and affinity of receptors can be
determined from a binding assay, in which
receptors are mixed with radioligands.

(3) Receptors can be isolated and
purified, then a functional system
reconstituted using the purified receptor
and transduction machinery.
b. Identifying specific neurotransmitters
or receptors in the CNS
(1) Immunocytochemistry.
(2) In situ hybridization uses
radiolabeled DNA to localize mRNAs
specific for particular proteins.

(3) Autoradiography employs:
Information obtained is similar to that
obtained using immunocytochemistry.
(4) High performance liquid
chromatography (HPLC).
(5) Neural tracts may be identified by
intracellular dye injections, selective
lesioning, retrograde labeling with
horseradish peroxidase, or anterograde
labeling with certain lectins.

III. BIOLOGIC AMINES
A. Dopamine
1. Synthesis
Tyrosine hydroxylation is the rate-limiting step
in the synthesis of all major catecholamines
(i.e., dopamine, norepinephrine, and
epinephrine).
2. Metabolism
a. Two enzymes are important for the
inactivation of catecholamines.
(1) Monoamine oxidase (MAO) is located on the
outer membrane of the mitochondria
oxidative deamination of intracellular, extra
vesicular catecholamines.

Two forms of MAO exist. Dopamine is deaminated
by both forms.
(a) MAO-A deaminates norepinephrine and
serotonin.
(b) MAO-B deaminates β-phenylethylamine and
benzylamine.
(2) Catechol-O-methyltransferase (COMT) is
found on the outer plasma membranes of most
cells. COMT methylates most extracellular
catecholamines.
b. A major metabolite of dopamine in urine and
plasma is homovanillic acid (HVA), which is
formed through the action of both MAO and
COMT, in either order.

3. Receptors
The action of dopamine is either inhibitory or
excitatory. Inhibition is the more common
effect.
There are five types of dopamine receptors:
a. D1 receptors are generally postsynaptic and
activate adenylate cyclase.
b. D2 receptors are both postsynaptic and
presynaptic
The therapeutic efficacy of antipsychotic drugs are
correlated strongly with their affinities for the D2
receptor, implicating this subtype as an important
site for the action of antipsychotic drugs.

c. The three additional dopamine receptors are: D3,
D4, and D5 dopamine receptors.
Based on their regional brain distributions and
primary effector mechanisms, the D3 and D4
receptors are D2-like, and D5 are D1-like.
4. Important brain tracts
a. Major dopaminergic tracts (pathways)
(1) Nigrostriatal tract
Runs from the pars compacta of the substantia nigra
to the striatum.
This pathway is important in the initiation of
movement as its destruction causes a reduction or
loss of movement.

(2) Mesolimbic and mesocortical tracts
The dopaminergic neurons that form these
tracts are found in the ventral tegmental
area of Tsai, which lies superior and medial
to the substantia nigra.
The neurons project to the limbic system –
including the amygdala, nucleus
accumbens, septum, and cingulate gyrus –
and to the cerebral cortex, predominantly to
the frontal lobes.
These tracts are important in affect,
cognition, and motivation.

(3) Tuberoinfundibular (tuberohypophyseal) tract
The dopaminergic neurons of this tract are located in
the arcuate and periventricular nuclei of the
hypothalamus and project to the median eminence
of the hypothalamus and to the intermediate lobe of
the pituitary gland.
Dopamine is thought to be important in the
regulation of prolactin release.
(4) Medullary periventricular tract
Dopaminergic cell bodies are located in the motor
nucleus of the vagus nerve projecting to the
periventricular and periaqueductal gray areas,
the reticular formation, and the spinal cord gray
areas.

(5) Incertohypothalamic tract
A small group of neurons in the zona incerta
project from the dorsal posterior hypothalamus
to the dorsal anterior hypothalamus and to the
septum.
b. Other sites
Dopaminergic neurons are also located in the
interplexiform cells of the inner nuclear layer of
the retina and in the periglomerular cells of the
olfactory bulb.
These neurons lack axons and make connections
via dendrodendritic synapses.

5. Effects on behavior
From a behavioral perspective, the most
important dopaminergic tracts are the
nigrostriatal, mesolimbic, and
mesocortical tracts.
a. Parkinsonism and other movement
disorders
Normal control of voluntary movements
relies on a balance between
dopaminergic and cholinergic
components of the basal ganglia.

(1) The nigrostriatal tract degenerates in
Parkinson’s disease, resulting in the
clinical picture of akinesia, tremor, rigidity,
and loss of postural reflexes.
(2) Neuroleptic drugs (because they block
postsynaptic dopamine receptors) and
reserpine (because it depletes dopamine)
also cause Parkinsonism.
(3) Certain hyperkinetic disorders (e.g.,
Huntington’s disease, tardive dyskinesia)
are related to a relative excess of
dopamine transmission.

Tardive dyskinesia occurs after long-term
treatment with neuroleptic drugs and
usually appears as choreoathetoid
movements of the mouth and hands.
(a) Tardive dyskinesia: long-term treatment
with neuroleptic drugs causes super-
sensitivity of postsynaptic D2 receptors.
(b) This hypothesis has been questioned and
may not explain the development of tardive
dyskinesia only in some patients.

b. Schizophrenia
Dopamine is also important for the organization
of thought and feeling.
(1) Schizophrenia – a disorder marked by
hallucinations, delusions, thought disorder, and
inappropriate or blunted affect – is related to
abnormalities in dopamine transmission in the
mesolimbic and mesocortical areas of the brain.
This is known as the dopamine hypothesis of
schizophrenia. Dopaminergic abnormalities
alone do not account for the entire clinical
picture.

(2) The psychotic symptoms of schizophrenia result
from a hyperdopaminergic state, based on some of
the evidence listed below.
(a) The ability of neuroleptic drugs to block D2
receptors correlates significantly with their
antipsychotic potency.
(b) Drugs that enhance dopaminergic transmission
(e.g., amphetamine, L-dopa) tend to worsen
schizophrenic symptoms and can produce
hallucinations and delusions in normal individuals.
(c) Increased concentrations of dopamine and
dopamine receptor activity in patients with
schizophrenia.

B. Norepinephrine
1. Synthesis
2. Metabolism
a. Two metabolites of norepinephrine are
commonly measured in plasma or urine: 3-
methoxy-4-hydroxyphenylglycol (MHPG) and
3-methoxy-4-hydroxymandelic acid
(vanillylmandelic acid, or VMA). 30-40% of
urinary MHPG is formed in the brain. Both
MHPG and VMA are formed through the
oxidative deamination of norepinephrine
involving the enzyme MAO-A.

b. Norepinephrine is released into the
synaptic cleft from storage vesicles by the
process of exocytosis. After release, there
is an active reuptake process that removes
norepinephrine from the synaptic cleft.
3. Receptors
a. α1-Receptors are postsynaptic and act by
raising intracellular calcium.
Prazosin exerts a relatively selective α1-
receptor blockade.

b. α2-Receptors are mainly postsynaptic,
negatively linked to adenylate cyclase,
and decrease the synthesis of
norepinephrine in the presynaptic neuron
when stimulated. At low doses,
clonidine is an α2-agonist and piperoxan
and yohimbine are selective α2-
antagonists.
c. β1-Receptors are mainly postsynaptic
and are positively linked to adenylate
cyclase.

d. β2-Receptors are mainly postsynaptic and
also positively linked to adenylate cyclase.
e. In the periphery, β1-receptors are found
predominantly in the heart, whereas β2-
receptors are found mainly in the lungs, blood
vessels, and vascular beds in skeletal muscle.
f. Nonselective β-agonists and β-antagonists
(1) Nonselective β-agonists include epinephrine
and norepinephrine; these are equipotent on
β1-receptors, but epinephrine is much more
potent than norepinephrine on β2-receptors.

(2) Nonselective β-antagonists: propranolol,
alprenolol, nadolol, and timolol.
Two major groups of noradrenergic neuron
tracts exist in the brain.
a. The first group arises from the locus
ceruleus (“blue spot”), which is a cluster
of pigmented neurons located within the
pontine central gray area along the lateral
aspect of the fourth ventricle.

This nucleus sends projections to the
cerebellum and spinal cord and
through the median forebrain bundle
to the hippocampus, ventral striatum,
and entire cerebral cortex.
b. The second group of tracts originates
in the lateral ventral tegmental area
and projects to basal forebrain areas
such as the septum and amygdala.

a. Neuromodulatory functions
Noradrenergic axons projects to most areas
of the brain, and norepinephrine is likely
an important neuromodulators.
(1) Norepinephrine enhances locomotor
responses to dopamine; it plays a role in
various physiologic functions, including
the sleep-wake cycle, pain, anxiety, and
arousal.

(2) Norepinephrine system mediates an
organism’s orientation to the environment:
When unexpected external sensory stimuli
arise, norepinephrine neuronal firing
increases, whereas it decreases during
tonic vegetative activities.
b. Mood
Norepinephrine is important in the genesis
and maintenance of mood and may be
related to mood and anxiety disorders.

(1) The catecholamine theory of mood
disorders states that reduced activity of
catecholaminergic systems (usually the
noradrenergic system) in certain brain area
may be associated with depression and
higher activity with mania.
(a) Reserpine, which depletes
norepinephrine, causes a state similar to
depression.
(b) MAO inhibitors (e.g., iproniazid,
phenelzine) have antidepressant properties.

(c) Amphetamines, which cause the release of
norepinephrine, cause an elevation of mood.
(d) Tricyclic antidepressants increase the
availability of norepinephrine.
(e) Propranolol, a nonselective β-blocker,
causes symptom improvement in some patients
with mania, but also to worsen depression.
(2) There is some indirect pharmacologic
evidence of norepinephrine hyperactivity in
some schizophrenic patients and in patients
with anxiety disorders.

c. Movement disorders
Norepinephrine is involved in various
movement disorders [i.e., autosomal
dominant torsion dystonia, Parkinson’s
disease, Tourette’s syndrome (which is
marked by vocal and tics), akathisia (a
disorder of motor restlessness associated
with neuroleptic drugs)]. Some evidence
suggests noradrenergic hyperactivity in at
least a subset of patients with tardive
dyskinesia

C. Serotonin [5-hydroxytryptamine (5-HT)]
1. Synthesis
2. Metabolism
a. Serotonin catabolism involves oxidation
of the amino group, which is catalyzed by
MAO (primarily MAO-A), followed by
rapid oxidation to 5-hydroxyindoleacetic
acid (5-HIAA).
(1) Melatonin is an N-acetylated derivative of
serotonin that is made in the pineal gland.

(2) Apart from degradation, serotonin may be
inactivated by reuptake into the presynaptic
neuron, a process that is inhibited by tricyclic
antidepressants. Drugs such as reserpine and
tetrabenazine deplete serotonin from the
vesicles.
3. Receptors
a. Types
(1) 5-HT1 receptors preferentially bind serotonin
and are separated into several subclasses.
(a) 5-HT1A receptors, found in the hippocampus,
inhibit cyclic AMP production.

(b) 5-HT1B receptors, found in high density
in the striatum, function as autoreceptors.
(c) 5-HT1C receptors in the choroids plexus;
occupation of 5-HT1C receptors is linked to
phosphatidylinositol turnover
(2) 5-HT2 receptors preferentially bind
spiperone (a drug that is also a D2-
antagonist) and are thought to be more
important in mediating the behavioral effects
of serotonin. They are found in the
neocortex and hippocampus and in platelets

(3) 5-HT3 receptor produces rapid excitatory
effects in postsynaptic neurons. The receptor
is expressed within the hippocampus,
neocortex, amygdala, hypothalamus, and
brainstem motor nuclei. Outside the brain, it
is found in the pituitary gland, enteric nervous
system sympathetic ganglia, and in sensory
ganglia. 5-HT3 receptor antagonists such as
ondansetron (Zofran) have been used as anti-
emetic agents and are under evaluation as
potential anti-anxiety and cognitive-
enhancing agents.

(4) Other serotonin receptors: recently
identified 5-HT4; 5-HT5, including subtypes 5-
HT5A and 5-HT5B; 5-HT6 and 5-HT7
receptors.
(5) Presynaptic serotonin receptors also exist.
LSD acts as both a receptor blocker and a
partial agonist, and it exerts more potent effects
on presynaptic serotonin receptors.
b. Actions
The predominant action of serotonin on receptors
is inhibition, although excitation has been
described in some cases.

The most important serotonergic neurons in
the brain are located in clusters in or around
the middle, or raphe, of the pons and
mesencephalon, including the median and
dorsal raphe nuclei.
a. The median raphe neurons innervate limbic
structures including amygdala.
b. The dorsal raphe neurons innervate the
striatum, cerebral cortex, thalamus, and
cerebellum.

Serotonin is important for many central
processes, including pain perception,
aggression, appetite, thermoregulation, blood
pressure control, heart rate, and respiration. It is
important for induction of sleep and
wakefulness.
a. mood disorders
(1) It has been suggested that low activity of
serotonin in the brain is associated with
depression, whereas high activity is associated
with mania.

(2) Another theory, known as the
permissive serotonin hypothesis,
states that lowered serotonin activity
“permits” low levels of catecholamines
to cause depression and high levels to
cause mania.
(3) Some serotonin reuptake blockers
(e.g., fluoxetine, fluvoxamine) are
powerful antidepressants.

b. Schizophrenia
The transmethylation hypothesis of
schizophrenia asserts that certain methylated
derivatives of serotonin, formed as a result of
errors in metabolism, may cause psychosis.
(1) This theory is supported by the finding that
LSD and serotonin derivatives (e.g.,
dimethyltryptamine, harmaline, psilocybin)
cause hallucinations and behavioral
abnormalities.
c. Serotonin also probably is involved in OCD.

D. Histamine
1. Synthesis
2. Metabolism
Histamine is methylated to methyl-histamine and
subsequently is oxidized to 1,4-
methylimidazoleacetic acid.
3. Receptors
There are three types of histamine receptors, H1,
H2, and H3. They exist in the brain and in the
periphery. H1 and H2 receptors activate
adenylate cyclase.

Histamine H1 and H2 receptors are excitatory in
the hypothalamus, hippocampal formation,
and thalamus; it is mainly inhibitory in the
cerebral cortex.
a. Histamine type 1 (H1) receptors are expressed
throughout the body, in smooth muscle of the
GIT and blood vessel walls. H1 receptors are
widely distributed throughout the CNS.
b. H2 receptors are widely distributed
throughout the body, and are found in gastric
mucosa, smooth muscle, cardiac muscle, and
cells of the immune system.

Within the CNS, H2 receptors are abundantly
expressed in the neocortex, hippocampus,
amygdala, and striatum. H2 receptor antagonists
are widely used in the treatment of peptic ulcer
disease.
c. Unlike H1 and H2 histamine receptors, H3
receptors are located presynaptically on axon
terminals. Those located on histaminergic
terminals act as autoreceptors to inhibit histamine
release.
H3 receptors are also located on nonhistaminergic
nerve terminals, where they inhibit the release of
a variety of neurotransmitters.

Particularly high levels of H3 receptor
binding are found in the frontal cortex,
striatum, amygdaloid complex, and
substantia nigra.
Lower levels are found in peripheral tissues
such as the gastrointestinal tract, pancreas,
and lung.
Antagonists of H3 receptors have been
proposed to have appetite suppressant,
arousing, and cognitive-enhancing
properties.

Histamine is found in high concentrations in
the mesencephalon, hippocampus, thalamus,
basal ganglia, and cerebral cortex.
Histamine is important in arousal, water
intake, vasopressin release,
thermoregulation, and cardiovascular
function.
Blockade of histamine receptors leads to
weight gain, sedation, and hypotension.

a. Anorexia nervosa, an illness
characterized by excessive weight loss, has
been reported to be treated successfully
with cyproheptadine, a drug that blocks H2
receptors (it also blocks5-HT receptors).
b. The tricyclic antidepressant doxepin, in
addition to being a serotonin agonist, also
has powerful H1- and H2-receptor-
blocking abilities, although it is not clear
how this relates to its antidepressant
potential.

IV. ACETYLCHOLINE
A. Synthesis
Choline cannot be synthesized in neurons;
it is transported into the brain by high-
affinity and low-affinity transport
processes.
The high-affinity process, which is
inhibited by hemicholinium-3, is the
primary factor regulating the amount of
ACh present in neurons.

B. Metabolism
ACh is inactivated by cholinesterases, including
pseudo-cholinesterase and
acetylcholinesterase; the latter is reversibly
inhibited by physostigmine and almost
irreversibly inhibited by organophosphorus
compounds such as those used in insecticides.
C. Receptors
The two main types of ACh receptors – nicotinic
and muscarinic receptors – both occur in the
brain.

1. Nicotinic receptors are channels allowing sodium to
enter the neuron. Therefore, they are excitatory.
a. Sites
(1) Nicotinic receptors in the peripheral nervous system
are located on the cell bodies of postganglionic
neurons of both the sympathetic and parasympathetic
divisions of the ANS.
(2) Also are located at the junctions of motor nerves and
skeletal muscle.
(3) In the brain but less is known about them than about
muscarinic receptors.
b. Nicotinic receptor agonists include nicotine, and
antagonists include curare drugs.

2. Muscarinic receptors may be excitatory or
inhibitory. Presynaptic ACh receptors are mainly
muscarinic.
a. Sites
Muscarinic receptors are located in the peripheral
ganglia of both the sympathetic and parasympathetic
nervous system.
They also are located on the end organs of the
parasympathetic nervous system (i.e., smooth muscle
and glands).
b. Muscarinic receptor agonists include muscarine (a
mushroom alkaloid), pilocarpine, and oxotremorine.
Antagonists include atropine.

c. Types
Muscarinic receptors are divided into two types,
M1 and M2.
(1) M1 receptors are postsynaptic and
excitatory and are widespread throughout the
neocortex.
(2) M2 receptors are concentrated in the cortical
laminae that demonstrate the greatest choline
acetyltransferase activity.
They are presynaptic and modulate the release
of ACh, probably through inhibition of
adenylate cyclase.

D. Important brain tracts
There is an important cholinergic pathway from
the basal forebrain (the nucleus basalis) to the
hippocampus and probably to the cerebral
cortex. The striatum is rich in ACh, where it is
found mainly in short intrastriatal neurons.
E. Effects on behavior
In animals, ACh is believed to be important in
movement, sleep, aggression, exploratory
behavior, sexual behavior, and memory. For
humans, the most important effects involve
movement and memory.

1. ACh is important in movement both peripherally
and centrally.
a. Peripherally
ACh is the main transmitter for skeletal muscles;
many powerful neurotoxins (e.g., curare, α-
bungarotoxin) paralyze by blocking ACh receptors.
b. Centrally
ACh and dopamine exist in reciprocal balance in the
extrapyramidal motor system. A decrease in one
(e.g., a decrease in dopamine in Parkinson’s disease)
can be offset somewhat by decreasing the other
(e.g., by using anticholinergic drugs).

2. ACh also is important in memory and
cognition
Dementing illnesses such as Alzheimer’s
disease is associated with a loss of
cholinergic transmission in the brain – both
to the hippocampus and to the cerebral
cortex.
A decreased number of cholinergic neurons in
the nucleus basalis of Meynert (located in the
basal forebrain) has been reported in patients
with Alzheimer’s disease and certain other
dementing disorders.

V. AMINO ACIDS
A. Inhibitory neurotransmitters
1. GABA
It has proved to be purely inhibitory in all
studies to date.
Unlike most other neurotransmitters, GABA
is limited almost entirely to the CNS.
Present in as many as 60% of synapses,
GABA is 200 to 1000 times more abundant
than dopamine, ACh, norepinephrine, and
other transmitters.

a. Synthesis
b. Metabolism
GABA is catalyzed by GABA transaminase to
succinic semialdehyde, which is oxidized to
succinic acid, which enters the citric acid cycle.
c. Receptors
At least two types of GABAergic receptors exist
in the CNS.
(1) GABA-A receptors are the classic
postsynaptic GABA receptors. Muscimol is a
selective agonist, and bicuculline (a convulsant)
and picrotoxin are selective antagonists.

(a) Some GABA-A receptors are coupled to a
recognition site for benzodiazepines, which
potentiate GABA’s inhibitory action.
(b) Benzodiazepine receptors exist in two forms.
(2) GABA-B receptors: Baclofen, a drug used
to treat spasticity, is a selective agonist.
d. Important brain tracts
Many brain pathways contain GABA.
(1) GABA is the primary neurotransmitter for
Purkinje cells, which are the only efferent
neurons for the entire cerebellar cortex.

(2) Inhibitory interneurons in almost all
areas of the brain contain GABA.
(3) GABAergic pathways extend from the
striatum to the substantia nigra and to the
globus pallidus, which may be important
in movement disorders such as
Parkinson’s and Huntington’s diseases.
(4) GABAergic pathway extends from the
magnocellular neurons of the posterior
hypothalamus to the neocortex.

2. Glycine structurally is the simplest amino
acid.
a. Like GABA, glycine is an inhibitory
neurotransmitter.
Its action is much more restricted than that
of GABA, however, as it is found only in
the brain stem and spinal cord and,
possibly, in the retina and diencephalons.
b. Strychnine blocks the action of glycine.
3. Other possibly inhibitory amino acids
include alanine, cystathionine, and serine.

B. Excitatory neurotransmitters
The only amino acids act as excitatory
neurotransmitters are glutamate and
aspartate. These neurotransmitters, as
well as some of their analogs (e.g., kainic
acid), are neurotoxic under certain
conditions.
1. Synthesis
Both glutamate and aspartate can be
synthesized from glucose.

2. Receptors
There are multiple receptor subtypes for
glutamate.
a. Kainate receptors and quisqualate receptors
operate to allow the influx of sodium; N-methy-
D-aspartate (NMDA) receptors, which
normally are blocked by physiologic
concentrations of magnesium, open to allow
sodium and calcium into the cell upon
depolarization.
b. Phencyclidine (PCP), a common drug of abuse,
is an antagonist at the NMDA receptor and has
effects on the σ-opioid receptor.

Glutamate exists in the corticostriatal pathway
and in cerebellar granule cells, and that
aspartate exists in the hippocampal
commissural pathway.
Glutamate and aspartate may be the primary
excitatory transmitters of the brain.
a. Glutamate, especially via NMDA receptors,
may be involved in long-term potentiation of
neurons in the hippocampus, a process
important for memory storage.

b. It also is important for kindling, where repeated
subthreshold electrical stimulation eventually
results in a seizure.
VI. Other Non-peptide Neurotransmitter
Candidates
A. Prostaglandins and thromboxanes
1. Synthesis and biochemistry
They belong to a family of substances known as
eicosanoids, which are products of arachidonic acid
metabolism.
a. These hormone-like substances are among the most
abundant of autacoids (i.e., compounds synthesized
at or close to their sites of action

b. Prostaglandins and thromboxanes exist in
every tissue and body fluid, their synthesis is
increased in response to widely varied stimuli,
and they have diverse and complicated biologic
actions.
2. Nervous system effects
a. Prostaglandins do not appear to function as
neurotransmitters, but they may play a
neuromodulatory role.
Prostaglandin E2 act to inhibit the stimulated
release of dopamine and norepinephrine. PGE2
modulates the serotonin system.

b. Eicosanoids are released from brain tissue
following ischemia or trauma and may
contribute to the development of edema and to
deterioration of blood-brain barrier.
B. Purines
1. ATP may function as a neurotransmitter in the
intrinsic, nonadrenergic, noncholinergic neurons
of visceral smooth muscle.
2. Adenosine may serve as an inhibitory
neuromodulators of excitatory cells in the
cerebellum, hippocampus, medial geniculate
body, and septum.

Adenosine receptors also are found in the striatum,
where adenosine may help modulate
dopaminergic transmission.
VII. NEUROPEPTIDES
- Neuropeptides function principally as
neurohormones.
- They are important in
psychoneuroendocrinology.
- They may serve as neuromodulators and, in
some cases, as neurotransmitters (their course of
action is much slower than that of ACh,
dopamine, and norepinephrine).

- Peptides coexist with the simpler (“classic”)
transmitters within a single neuron, which
contradicts Dale’s principle.
A. Endogenous opioids
1. Overview and terminology
a. Opium has been used as a pain reliever and
psychotomimetic drug for millennia. In the
nineteenth century, it was determined that
most of this action is due to the alkaloid
morphine.

b. In the 1970’s, a class of endogenous
neuropeptides that bind to receptors that
mediate response to opioids named
enkephalins (meaning “in the head”).
Other substances called endorphins (a
contraction of “endogenous” and “morphine”).
c. Enkephalins and endorphins are called the
endogenous opioids.

2. Endogenous opioids families
Numerous endogenous opioids have been
identified, which fall into one of three families:
enkephalins [e.g., methionine and leucine
enkephalin (met- and leu-enkephalin)],
endorphins (e.g., α-, β-, and γ-endorphins), and
dynorphins (e.g., dynorphin A, dynorphin B).
3. Opioid receptors
a. Mu (μ) receptors mediate supraspinal
analgesia, respiratory depression, and euphoria.
Morphine and met-enkephalin are agonists at
these receptors.

b. Kappa (κ) receptors mediate spinal
analgesia and papillary miosis. Dynorphins are
agonists at these receptors.
c. Delta (δ) receptors in the CNS are associated
with mood components of opioid action. Leu-
enkephalin is an agonist at these receptors.
d. Epsilon (ε) receptors may produce catatonia.
β-endorphin is an agonist at these receptors.
e. Sigma (σ) receptors are associated with
psychotomimetic effects of certain opiates.

a. Many behavioral states and neuropsychiatric
disorders, including thermoregulation, seizure
induction, alcoholism, schizophrenia, general
effects on locomotion (especially hypomotility
and some movement disorders), and analgesia,
are associated with alterations in endogenous
opioids, particularly β-endorphin.
b. The treatment with opiate antagonists (e.g.,
naloxone, naltrexone): in the case of narcotic
overdose & may be helpful in some cases of
self-mutilatory behavior.

B. Gut peptides
They are found in both the brain and the
digestive tract.
1. Substance P has been found in the spinal
cord, substantia nigra, striatum, amygdala,
hypothalamus, and cerebral cortex.
a. Substance P may be the principal
neurotransmitter for the primary afferent
sensory fibers that travel through the dorsal
roots to the substantia gelatinosa of the spinal
cord and carry information about pain.

b. It also may be involved in a major
excitatory outflow tract from the
striatum to the substantia nigra and
globus pallidus and, thus, be important
for movement.
Substance P abnormalities have been
implicated in the pathophysiology of
Huntington’s disease, a hereditary
movement disorder in which its levels
have been reported to be reduced.

2. Cholecystokinin (CCK) is a polypeptide that is
released from the gut in response to chime, amino
acids, fats, and other substances, whereupon it
stimulates gallbladder motility and secretion of
pancreatic enzymes.
CCK is found in the hippocampus, neocortex, brain
stem, basal ganglia, hypothalamus, and amygdala.
a. Behaviorally, CCK may be associated with satiety.
b. CCK coexist with dopamine in neurons in the
ventral tegmental area of the brain stem and in the
nucleus accumbens – brain regions that are thought
to be important in the pathophysiology of
schizophrenia.

3. Vasoactive intestinal polypeptide (VIP)
is a 29-amino acid peptide originally
discovered in the intestine and named for
its ability to alter blood flow in the gut.
a. VIP is extremely common in the
neocortex, where it has been found in a
distribution indicating the VIP neurons may
be localized to single cortical columns.
b. VIP appears to be excitatory in action and
to be coupled with cAMP.

4. Somatostatin
a. It is found in the GIT, in the islets of
Langerhans, and in several areas in the
nervous system.
b. Its hormonal actions include suppression
of the release of GH and TSH in the brain
and suppression of the release of glucagon
and insulin in the pancreas.
c. It is thought to be important in the
production of slow wave sleep and REM
sleep, in appetite, and in motor control.

d. Somatostatin injection in animals is
associated with decreased spontaneous
motor activity.
e. Increased Somatostatin levels have been
reported in the corpus striatum of patients
with Huntington’s disease, whereas
decreased levels have been reported in the
cortex of patients with Alzheimer’s
disease.
f. Somatostatin may modulate the activity of
the nigrostriatal dopamine tract.

5. Neurotensin is found in the substantia
gelatinosa of the spinal cord, the brain stem
(especially in the motor nucleus of the
trigeminal nerve and substantia nigra),
hypothalamus, amygdala, nucleus accumbens,
septum, and anterior pituitary gland.
- Neurotensin is excitatory and may play a role in
arousal, thermoregulation, and pain perception.
- It is involved in the pathophysiology of
schizophrenia, mostly because of its coexistence
with dopamine in some axon terminals.

C. Pituitary, hypothalamic, and pineal
peptides
1. Overview
a. Pituitary hormones
The pituitary gland consists of two main lobes.
(1) The anterior pituitary secretes six
hormones, most of which have tropic
properties (i.e., they have an affinity for a
specific target gland). Its hormones include:
(a) ACTH (b) GH (c) TSH
(d) LH (e) FSH (f) Prolactin

(2) The posterior pituitary secretes vasopressin and
oxytocin.
(3) The intermediate lobe is vestigial in adult
humans. MSH is believed to be secreted from this
part of the pituitary gland in animals, but possibly
from the anterior pituitary in humans.
b. Hypothalamic hormones, or releasing factors,
control the release of anterior pituitary hormones.
The anterior pituitary hormones control the release
of hormones from target endocrine glands.
c. Pineal hormones: Melatonin is synthesized in the
pineal gland

2. ACTH (corticotrophin) is found in the limbic
system, brain stem, and thalamus and may be
important in learning, memory, and attention.
- ACTH regulates the release of cortisol; ACTH
is regulated by the CRF.
- The levels of both ACTH and cortisol exhibit a
diurnal variation, and cortisol levels peak at
approximately 7 A.M.
a. Excess amounts of cortisol are seen in
Cushing’s syndrome, which may be associated
with depression, mania, hallucinations,
delusions, and delirium.

b. A deficit of cortisol is seen in Addison’s
disease, which may be accompanied by
depression, lethargy, and fatigue.
c. A subset of patients with endogenous
depression have:
--- high cortisol levels,
--- loss of the normal diurnal variation in cortisol
levels,
--- and “early escape” from suppression of cortisol
secretion following administration of
dexamethasone in the dexamethasone
suppression test.

Some patients with mania, schizoaffective,
bulimia, or anorexia nervosa may also exhibit
these findings. Suppression of cortisol levels
during the dexamethasone suppression test,
however, indicate the presence of antidepressant-
responsive endogenous depressive illness.
3. GH (somatotropin) increases protein synthesis,
decreases the utilization of carbohydrates, and
facilitates the mobilization of fats.
--- GH secretion and synthesis are controlled by
GH-RF and GH-release inhibiting factor
(somatostatin).

--- GH exhibits a diurnal pattern of
release, with higher levels secreted
during sleep.
a. The somatic effects of GH appear to
require the involvement of a family of
polypeptides called somatomedins.
b. Norepinephrine, dopamine, and
serotonin alter GH concentrations, and
stress causes increased release of GH.

4. TSH (thyrotropin) causes the release of the
thyroid hormones T3 and T4. The release of
TSH is controlled by TRH.
a. TRH is localized in the dorsomedial and
periventricular nuclei of the hypothalamus.
b. TRH is inhibitory to postsynaptic neurons
and, apart from its effects on thyroid function,
is involved in mood and behavior.
Some patients with major depression show a
blunted TSH response to intravenous infusion
of TRH, which suggests hypothalamic-
pituitary dysfunction in major depression.

5. LH and FSH regulate ovarian follicle
growth, spermatogenesis, and testosterone
secretion. Release of LH and FSH from the
anterior pituitary is regulated by GnRH.
a. GnRH injection in males causes an increase
in sexual arousal, and injections have been
used with some success to treat delayed
puberty.
b. GnRH may function as a neurotransmitter as
well as a hormone, and it may be excitatory or
inhibitory.

6. Prolactin is controlled by PIF and PRF.
a. Prolactin regulates the activity of the mammary
glands during lactation. Sleep, exercise, pregnancy,
and breast-feeding increase circulatory levels of
prolactin.
b. Dopamine may function physiologically as PIF.
Most neuroleptic medications block dopamine
receptors in the tuberoinfundibular dopamine tract,
causing an increase in circulating prolactin and
therefore inducing beast enlargement and lactation.
This is a common side effect of neuroleptics in
women – which can also occur in men.

7. Vasopressin and oxytocin are formed
from larger precursor hormones known as
neurophysins.
a. Synthesis and release
They are synthesized in large neurons in the
supraoptic, & paraventricular nuclei of the
hypothalamus.
(1) The neurons from the supraoptic and
paraventricular nuclei project to the
posterior pituitary, where the hormones are
released into the circulation.

(2) The release of vasopressin (ADH) is
increased by stress, pain, exercise, and a
variety of drugs (e.g., morphine, nicotine,
barbiturates). Alcohol decreases its
release, resulting in diuresis.
(3) The release of oxytocin is stimulated by
estrogens, vaginal and breast stimulation,
and psychic stress.
-- Oxytocin release is inhibited by severe
pain, increased temperature, and loud
noise.

b. Effects
(1) Vasopressin is mainly inhibitory and may be
important in learning, memory, and
attention. Treatment with vasopressin
improves memory in patients with dementia
and brain damage.
(2) Oxytocin
(a) The main peripheral effects of oxytocin
include stimulation of the myoepithelial cells
lining ducts of the beast – causing expression
of milk – and inducing contraction of uterine
smooth muscles during parturition.

(b) Centrally, oxytocin may be an inhibitory
neurotransmitter or neuromodulators and may
act in a way opposite to vasopressin in terms
of its effects on memory, actually causing
amnesia.
8. MSH is structurally similar to ACTH. Its
release is regulated by dopamine and possibly
by MSH-inhibiting factor and MSH-releasing
factor.
a. MSH is found in the pituitary gland as well as
a number of other brain area, including the
hypothalamus, and cerebral cortex.

MSH is important in the control of pigmentation
in animals. It may have a role in learning and
memory. MSH and MSH-inhibiting factor have
both been reported to have antidepressant
effects.
9. Melatonin is synthesized from serotonin in the
pineal gland.
a. Melatonin has important neuroendocrinologic
effects. It is involved in the regulation of
circadian rhythms. Melatonin synthesis is
regulated by the day-night or light-dark cycle,
and levels are increased during darkness.

b. Because the pineal gland can transform information
contained in light into chemical information contained in
melatonin, the pineal gland has been called a
“neuroendocrine transducer”.
c. Some depressed patients show low nocturnal melatonin
levels.
d. In seasonal mood disorder, affected individuals have
regularly occurring seasonal depressions, usually in the
fall and winter. Early morning therapy with bright light
(phototherapy) has shown benefit and may be associated
normalization of the so-called dim-light onset of
melatonin secretion. The role of melatonin is seasonal
mood disorder, however, is far from clear.

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