dopamine serotonin noradrenaline adrenaline also acetylcholine

1. Dr. M.G.SRINIVAS
ROLE OF MONOAMINE
NEUROTRANSMITTERS
IN PSYCHIATRY

2. CONTENTS
 DISCOVERY OF 1ST NEUROTRANSMITTER
 DEFINITION OF NEUROTRANSMITTER
 CRITERIA FOR NEUROTRANSMITTER
 7 PROCESSESS IN NEUROTRANSMITTER
ACTION
 FATE OF NEUROTRANSMITTERS
 CLASSIFICATION OF NEUROTRANSMITTERS
 BIOGENIC AMINES
 DOPAMINE
 SEROTONIN
 EPINEPHRINE & NOREPINEHRINE
 HISTAMINE
 ACETYLCHOLINE

3. DISCOVERY OF 1st
NEUROTRANSMITTER
 Acetylcholine - The first neurotransmitter
identified, in 1926, by Otto Loewi.
 He demonstrated that Acetylcholine carried a
chemical signal from vagus nerve to the heart
that slowed the cardiac rhythm.
 Got NOBEL in physiology & medicine
in the year 1936

4. NEUROTRANSMITTERS
DEFINITION
 Neurotransmitters are chemical signals
released from presynaptic nerve terminals into
the synaptic cleft.
 The subsequent binding of neurotransmitters
to specific receptors on postsynaptic neurons
(or other classes of target cells) transiently
changes the electrical properties of the target
cells, leading to an enormous variety of
postsynaptic effects.

5. CRITERIA FOR NEUROTRANSMITTERS
1. Molecule is synthesized in neuron
2. Molecule is present in presynaptic neuron & is
released on depolarisation in physiologically
significant amount
3. When administered exogenously as a drug,
the exogenous molecule mimics the effect of
endogenous neurotransmitter
4. A mechanism in neurons or synaptic cleft acts
to remove or deactivate the neurotransmitter

6. MAJOR STEPS IN
NEUROTRANSMITTER PROCESSING
are:
1. SYNTHESIS
2. STORAGE
3. RELEASE
4. RECEPTION
5. INACTIVATION

8. FATE OF NEUROTRANSMITTERS
1. It is consumed ( broken down or used up) at
postsynaptic membrane leading to action
potential generation.
2. Degraded by enzymes present in synaptic
cleft.
3. Reuptake mechanism( reutilization), this is the
most common fate.

9. CLASSIFICATION OF
NEUROTRANSMITTERS

11. Amine neurotransmitters:
1. Catecholamines
Dopamine
norepinephrine
epinephrine
2. Indolamines
Serotonin (5-hydroxytryptamine; 5-HT)
3. Histamine
4. Acetylcholine

12.  All monoaminergic systems share common
anatomical features.
 Each has a cluster of cell bodies in a few
restricted sub cortical or brainstem regions,
which then send long and extensively branched
axonal processes into
multiple cortical and limbic target regions.
 The precise evolutionary reasons for this
organization are unclear, although it could in
principle allow monoaminergic systems to
coordinately control spatially distant brain

13. DOPAMINE

14. DOPAMINE HISTORY
 The function of DA as
neurotrasmitter was discovered
in1958 by arvid carlsson &
nils ake hillarp.
 ARVID CARLSSON got NOBEL
for physiology or medicine in
2000 for showing that DA is not
Just a precursor of NE & E but a
Neurotransmitter as well.

16. DOPAMINE
DEGRADATION

18. DOPAMINE PATHWAYS
5 dopamine pathways in the brain:
1. The MESOLIMBIC DA pathway,
2. The MESOCORTICAL DA pathway,
3. The NIGROSTRIATAL DA pathway,
4. The TUBEROINFUNDIBULAR DA
pathway,
5. The THALAMIC DA pathway
 DA pathways in the brain can explain the
symptoms of schizophrenia as well as the
therapeutic effects

20. (1) THE MESOLIMBIC DOPAMINE PATHWAY
projects from the midbrain ventral
tegmental area to the nucleus accumbens, a
part of the limbic system

23. MESOLIMBIC PATHWAY role in
-emotional
behaviour
-pleasure
-motivation
-reward

24. HYPERACTIVITY OF MESOLIMBIC
PATHWAY
-positive psychotic symptoms
accompanying mania, depression,
dementia.
INCLUDES:
-delusion
-hallucination
-aggression
-hostility
-euphoria in drug abusers

25. HYPO ACTIVITY OF MESOLIMBIC
PATHWAY
 lack of general motivation & interest,
 anhedonia
 negative symptoms,
 drug abuse.

26. (2) MESOCORTICAL DOPAMINE PATHWAY
projects from midbrain ventral tegmental area
& sends its axons to areas of the prefrontal
cortex
Dorsolateral
prefrontal cortex,
DLPFC
Ventromedial
prefrontal cortex,
VMPFC

29. MESOCORTICAL pathway
 dorsolateral prefrontal cortex role
-Regulates
cognition &
-Executive
functions
Hypofunction:
-Cognitive deterioration
-Negative symptoms in
schzophrenia

30. Ventromedial prefrontal cortex
Regulates-
emotions & affect
Hypo function-
affective & negative symptoms

31. (3) The NIGROSTRIATAL dopamine pathway,

33.  Chronic D2 blockade –leads to neuroleptic
induced Tardive dyskinesia

34. (4) TUBEROINFUNDIBULAR DA PATHWAY

36. TUBEROINFUNDIBULAR DA PATHWAY
Activity - decrease in prolactin release
• Postpartum- increase in prolactin
• Antipsychotics - increase in prolactin
-galactorrhoea
-amenorrhoea
-sexual
dysfunction

37. (5) THALAMIC DA PATHWAY
arises from multiple sites,
-periaqueductal gray,
-ventral
mesencephalon,
-hypothalamic
nuclei, &
-lateral parabrachial
nucleus,
projects to the thalamus.
 Function is not currently well known.
 In primates it involves in sleep & arousal
mechanisms
No evidence of it’s involvement in

38. DOPAMINE RECEPTORS.
5 Types – D1, D2, D3, D4, D5.
2 Groups
D1 Like
D2 Like
D1, D5 D2,
D3,D4
Cyclic AMP Cyclic
AMP
D2-
Striatum

39.  -D2 receptor was initially distinguished from
the D1 receptor on the basis of its high affinity for
butyrophenones
 Moreover D2 receptor stimulation was observed
to inhibit rather than stimulate adenylate cyclase
activity.
 Unlike D1-like receptors, D2 receptor may have
either a postsynaptic function or an auto receptor
function

40. D2 auto receptors may be found on
dopaminergic terminals or on the cell bodies and
dendrites of dopaminergic neurons, where they
mediate the inhibition of evoked dopamine
release and the inhibition of dopaminergic
neuronal firing.
Furthermore, the over expression of striatal D2
receptors during brain development can cause
long-lasting defects in prefrontal dopaminergic
transmission and working memory in mice, a
finding relevant to neurodevelopmental
hypotheses of schizophrenia.

41.  D2 receptors are also expressed in the anterior
pituitary and mediate the
-dopaminergic inhibition of prolactin
and
-a-melanocyte-stimulating hormone
release.
 Molecular cloning has revealed long and short
forms of the D2 receptor
 Auto receptor functions are mediated by the
short form of this receptor

42. • Catalepsy induced by neuroleptics such as
haloperidol appears to be largely mediated by the
long form of the D2 receptor
• Post mortem analyses of schizophrenic
brains reveals elevations in D2 receptor
density.
• Furthermore, radioligand binding studies have
revealed
-a correlation between the clinical
efficacy of antipsychotic drugs and their
antagonist affinities for this receptor subtype.

43.  This finding has contributed significantly to
the “dopamine hypothesis” of
schizophrenia.
The extrapyramidal side effects of
antipsychotic drugs have been attributed to
blockade of striatal D2 receptors.

44. D3, D4 receptors
•D3 receptor expression is highest in the nucleus
accumbens.
The highest levels of D4 receptors are expressed
in -frontal cortex,
-midbrain,
-amygdala,
-hippocampus, and medulla
D4 receptors are abundant in the heart and
kidney.

45.  The D3 receptor may play a role in the control
of locomotion.
 Elevated D4 receptor levels have been found in
post-mortem schizophrenic brains.
 Moreover, the atypical antipsychotic drug
clozapine has a high affinity for the D4 receptor.

46. SEROTONIN

47. IMPORTANT PERSONALITIES IN
DISCOVERY OF SEROTONIN
A.BETTY
TWAROG
B.ARDA
GREEN
C.MAURICE
RAPPORT
D. IRVINE
PAGE

48. Dr. VITTORIO ERSPAMER
(1909 – 1999)

49. SEROTONIN
2% in CNS
98% in PERIPHERY
5HT Cannot cross B.B.B.
80% in G.I. Tract(motility
& contractility)
15-18% in Mast cells &
platelets(aggreg. & clotting)
-

50. Serotonin Synthesis & degradation

52. SEROTONIN PATHWAYS
 Clustered in midline raphe nuclei of
brainstem
1)ROSTRAL NUCLEI- sends
ascending axonal projections throughout the
brain
2)CAUDAL NUCLEI – sends
projections to medulla, cerebellum & spinal cord
• Innervation of dorsal horns – implicated in
suppression of noceceptive pathways, relate to

54. Rostral System:
 The Rostral midbrain cluster of cells (raphe
nuclei) are distributed throughout the midbrain, it
provides over 80% of the 5-HT innervation of the
forebrain.
 Sends projections to –Prefrontal cortex,
-basal forebrain,
- striatum,
-nucleus accumbens,
-thalamus,
-hypothalamus,
-amygdala,
-hippocampus

55.  A cluster of cells located medially and another
located dorsally
 MEDIAN RAPHE NUCLEUS: sends projections
predominantly to Limbic system including
hippocampus.
 DORSAL RAPHE NUCLEUS: sends
predominantly to striatum & thalamus.
 Projections from these nuclei course through
the MEDIAN FOREBRAIN BUNDLE before
diverging to many regions.
Innervation of forebrain structures by
serotonergic processes is complementary to that

56. OTHER SYSTEMS:
 In addition to the above two pathways,
another 5-HT pathway projects partially from
one of the Rostral nuclei and partially from
two caudal nuclei to innervate the cerebellar
cortex and deep cerebellar nuclei.
 There is also a widespread 5-HT projection
to structures within the brainstem, including
the locus coeruleus, several cranial
nuclei, inferior olivary nucleus, and
nucleus solitarius.

57. SEROTONIN RECEPTORS
 7 types of serotonin receptors are now
recognized:
5-HT1 through 5-HT7, with numerous
subtypes, totaling 14 distinct receptors
 The 5-HT1- is the largest serotonin receptor
subfamily,
5-HT1A,
5-HT1B,
5-HT1D,
5-HT1E, &
5-HT1F
 The most intensively studied of these has been

58. 5HT1A
 Postsynaptic membranes of forebrain neurons
primarily in the
-hippocampus,
-cortex,
-septum and
-on serotonergic neurons,
• Where it functions as an inhibitory
somatodendritic auto receptor
•There is significant interest in the 5-HT1A
receptor as a modulator of both anxiety and
depression

59.  The down regulation of 5-HT1A auto receptors
by the chronic administration of serotonin
reuptake blockers has been implicated in their
antidepressant effects
 SSRIs may produce some behavioral effects via
increase in hippocampal neurogenesis
mediated by postsynaptic 5-HT1A receptor
activation.
 Partial 5-HT1A receptor agonists such as
buspirone display both anxiolytic and
antidepressant properties.

60. 5HT1B & 5HT1D
 Resemble each other in structure and brain
localization, although the 5-HT1D receptor is
expressed at lower levels.
5HT1B -implicated in the modulation of loco
motor activity levels, consistent with its high
level of expression in basal ganglia -also been
suggested as a modulator of aggression,
although 5-HT1B receptor agonist drugs have
shown limited clinical efficacy as anti aggressive
agents.

61.  In addition, 5-HT1B and the 5-HT1D receptors
are found in the cerebral vasculature and the
trigeminal ganglion, respectively, and are
stimulated by
the anti migraine drug sumatriptan.
 These receptors may therefore be involved in
the therapeutic efficacy of this drug, possibly
mediating vasoconstriction and inhibition of
noceceptive transmission.

62. 5-HT1E Receptors
-striatum and
-entorhinal cortex,
5-HT1F Receptors
-dorsal raphe nucleus,
-hippocampus,
-cortex, and
-striatum.

63.  5HT2A Receptors
-neocortex
-platelets and
- smooth muscle
•Much recent attention has focused on the
contributions of 5-HT2A/C receptors to the
actions of atypical antipsychotic drugs such as
clozapine, risperidone and olanzapine.
•5-HT2A receptor has also been implicated in the
cognitive process of working memory, a function
believed to be impaired in schizophrenia.

64. 5-HT2B,
-contributes to the contractile effects
of serotonin in the stomach fundus and plays
important roles in cardiac development.

65.  5HT2C Receptors
-hippocampal formation,
-prefrontal cortex,
-amygdala,
-striatum,
-hypothalamus, &
-choroid plexus
 Stimulation of 5-HT2C receptors has been
proposed to produce anxiogenic effects as well
as anorectic effects, which may result from
interactions with the
hypothalamic melanocortin and leptin pathways.

66. 5-HT2C
-also play a role in the weight gain and
development of type II diabetes mellitus
associated with atypical antipsychotic treatment.
 Alterations in 5-HT2C receptor mRNA editing
have been found in the brains of suicide victims
with a history of major depression, and SSRIs
have been shown to alter these editing patterns.

67. 5HT3
-hippocampus,
-neocortex,
-amygdala,
-hypothalamus,
-brainstem, including the area postrema.
 Peripherally-pituitary gland and enteric nervous
system
 5-HT3 receptor antagonists such as
ondansetron are used as antiemetic agents and
are under evaluation as potential antianxiety and
cognitive-enhancing agents.

68. 5HT4 –Partial agonists used in IBS
(TEGASEROD)
5HT5, 5-HT6, 5HT7 receptors – Unclear action
-Antagonists may have
antidepressant action

69.  Serotonin is a key regulatory of
appetite,
sleep,
and
aggression.

70. ROLE IN PSYCHIATRY

71. Affective Disorders:
 Low levels of 5-HT and metabolites are
associated severe depression
 Recent studies indicate that this type of 5-HT
influence may start early in life; low levels of
5HIAA have been found in children and
adolescents with disruptive behavioral disorders.
Obsessive Compulsive Disorder: 5-HT
dysfunction has been associated with obsessive
compulsive disorder. Accordingly, selective 5-HT
uptake blockers are used as a therapy for this
condition.

72. Schizophrenia: Antipsychotic drugs are
producing favourable results in treating the
symptoms of schizophrenia.
These drugs are interesting pharmacologically in
that they block both DA and 5-HT receptors as well
as ACh and HA.
Migraine Headaches. 5-HT1 agonists are
used for the treatment of migraine headache.
Insomnia. The role of 5-HT in sleep regulation
has lead to the hypothesis that reduced levels of
5-HT may induce insomnia.

73. Norepinephrine and Epinephrine

74.  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.
Norepinephrine and
Epinephrine

75. Dopamine
↓Dopamine Beta-
Hydroxylase (DBH)
Norepinephrine
↓ (PNMT)
Epinephrine
-locus coeruleus is the origin of most
norepinephrine in the brain followed by the
lateral tegmental area .
-Levels of epinephrine in the CNS are only
about 10% of the levels of norepinephrine
-Norepinephrine, as with other
Catecholamines, itself cannot cross the blood-
brain barrier
SYNTHESI
S

76.  In neurons that release norepinephrine, the
enzyme dopamine β-hydroxylase converts
dopamine to norepinephrine; neurons that
release dopamine lack this enzyme.
 In neurons that release epinephrine, the
enzyme phenyl ethanolamine-N-
methyltransferase (PNMT) converts
norepinephrine into epinephrine.
 Neurons that release either dopamine or
norepinephrine do not have PNMT.
 As with dopamine, the two major routes of
deactivation are uptake back into the
presynaptic neuron and metabolism by MAO
and COMT

77. PATHWAY
 The major concentration of noradrenergic (and
adrenergic) cell bodies that project upward in
the brain is in the compact locus coeruleus 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

79. NA & ADR RECEPTORS
 The two broad groups: α-adrenergic receptors
and the β-adrenergic receptors.
The advances of molecular biology have now sub
typed these receptors into
three types of α1-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).
 All α 1-receptors are linked to the
phosphoinositol turnover system.
α -receptors inhibit formation of cAMP, and
β -receptors stimulate formation of cAMP.

80. NE & DRUGS
 The psychiatric drugs that are most associated
with
norepinephrine are the classic antidepressant
drugs,
the tricyclic drugs.
 Venlafaxine(SNRI), bupropion, and
nefazodone: block the reuptake of
norepinephrine and serotonin into the
presynaptic neuron
MAO inhibitors: block the catabolism of
norepinephrine and serotonin.
• Thus, the immediate effect is to increase the
concentrations of norepinephrine and serotonin
in the synaptic cleft.

81. Antidepressants:
 Serotonin-norepinephrine reuptake inhibitor
(SNRIs): class of antidepressant for treatment of
depression, mood disorders, anxiety.
 Benzodiazepines, the primary antianxiety
drugs, decreases firing in the locus coeruleus
causing sleep
 The beta-adrenergic blocking drugs
(propranolol) act as antianxiety and inhibit the
formation of traumatic memories.

82. HISTAMINE

83. HISTAMINE SYNTHESIS
HISTIDINE
L histidine
decorboxylase
HISTAMINE
 This enzyme is not normally saturated with
substrate,
so synthesis is sensitive to histidine levels.
 Thus peripheral administration of histidine
elevates
brain histamine levels.

85. HISTAMINE: ANATOMY
-Histaminergic cell bodies
-the posterior
hypothalamus termed the tuberomammillary
nucleus
 project diffusely throughout brain and spinal
cord

87.  Ventral ascending projections
course through the medial forebrain bundle and
then innervate the hypothalamus, diagonal band,
septum, and olfactory bulb.
 Dorsal ascending projections
innervate the thalamus, hippocampus, amygdala,
and Rostral forebrain.

88.  Descending projections
• travel through the midbrain central gray to the
dorsal hindbrain and spinal cord.

89.  The hypothalamus receives the densest
histaminergic innervation, consistent with a role
for this transmitter in the regulation of autonomic
and neuroendocrine processes.
 Additionally, strong histaminergic innervation is
seen in monoaminergic & cholinergic nuclei.
 Histamine is distributed throughout most
tissues of the body, predominantly in mast cells.

90. HIATAMINE RECEPTORS
 Histaminergic systems have been proposed to
modulate
-arousal,
-wakefulness,
-feeding behaviour, and
-neuroendocrine responsiveness
 Four histaminergic receptor subtypes have
been identified and termed H1, H2, H3, and H4.

91.  H1 receptors are expressed throughout the
body, particularly in smooth muscle of the
gastrointestinal tract and bronchial walls as well
as on vascular endothelial
cells.
 H1 receptors are widely distributed within the
CNS, with particularly high levels in the
thalamus, cortex, and cerebellum. These
receptors are the targets of classical
antihistaminergic agents used in the treatment
of allergic rhinitis and conjunctivitis.

92.  The well-known sedative effects of these
compounds have been attributed to their actions
in the CNS and have implicated histamine in the
regulation of arousal
and the sleep–wake cycle.
H2 receptors
 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.

93. • H2 receptor antagonists are widely used in the
treatment of peptic ulcer disease.
•In contrast, the functional significance of central
H2 receptors is unclear, although several studies
indicate that the stimulation of these receptors
produces
antinociceptive effects.
•H2 receptors may also be involved in the control
of fluid balance, possibly along with H1 receptors,
via the stimulation of vasopressin release.

94. H3 receptors
 located presynaptically on axon terminals
Those located on histaminergic terminals act as
auto receptors to inhibit histamine release.
In addition, H3 receptors are located on
nonhistaminergic nerve terminals, where they act
as heteroreceptors to inhibit the release of a
variety of
neurotransmitters—including norepinephrine,
dopamine, acetylcholine, and serotonin.

95.  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.

96. The H4 receptor
Detected predominantly in the periphery, in
regions such as the spleen, bone marrow, and
leukocytes

97. Acetylcholine

98. Acetylcholine synthesis

99. Acetylcholine in the PNS
• Produced by:
– Motor neurons
– Parasympathetic
Both pre- and post-ganglionic neurons
– Sympathetic
pre-ganglionic neurons
some post-ganglionic neurons that
innervate sweat glands and blood
vessels

100. Central Cholinergic
Projections
• Basal forebrain
– Nucleus basalis (of Meynert),
septal nuclei. .
• Brainstem reticular formation
(“Ponto-mesencephalotegmental
complex”)
– Project to thalamus, brainstem,
basal forebrain
• Cholinergic interneurons
– caudate-putamen, n. accumbens

101.  In Alzheimer's disease there is significant
degeneration of neurons in the nucleus
basalis, leading to substantial reduction in
cortical cholinergic innervation
 Cholinergic neurons may continue to fire
during REM sleep and have been proposed
to play a role in REM sleep induction

102.  The modulation of striatal cholinergic
transmission has been implicated in
the anti parkinsonian actions of
anticholinergic agents.

103.  Peripheral acetylcholine mediates the
characteristic postsynaptic effects of the
parasympathetic system, including
bradycardia and reduced blood pressure,
and enhanced digestive function.
 Cholinesterase inhibitors are also used in
the treatment of myasthenia gravis, a
disease characterized by weakness due to
blockade of neuromuscular transmission
by auto antibodies to acetylcholine
receptors

104. CHOLINERGIC RECEPTORS

105.  Two major classes of cholinergic receptors
exist:
-G-protein-coupled muscarinic receptors
and
- Nicotinic ligand-gated ion channels

106.  In the periphery, muscarinic receptors
mediate the effects of postganglionic
parasympathetic nerve release of
acetylcholine.
 Central muscarinic receptors have been
implicated in learning and memory,
sleep regulation, pain perception,
motor control, and the regulation of
seizure susceptibility.
 Five muscarinic receptor subtypes have
been cloned, and these may be divided

107. Types of Receptors
 The M1, M3, and M5 receptors activate Gq,
leading to phosphatidylinositol turnover
and an increase in intracellular calcium
 The M2 and M4 receptors may act as
inhibitory autoreceptors and
heteroreceptors to limit presynaptic
release of neurotransmitters.

108. M1
 M1 receptors are the most abundantly
expressed muscarinic receptors in the
forebrain, including the cortex,
hippocampus, and striatum.
 Pharmacological evidence has suggested
their involvement in memory and synaptic
plasticity

109. M2
 In addition to being the predominant
muscarinic receptor subtype in the heart
where they function to lower heart rate, M2
receptors are widely distributed
throughout the brain
 M2 receptors appear to mediate tremor,
hypothermia, and analgesia induced by
muscarinic agonists

110. M3
 M3 receptors are found in smooth muscles
and salivary glands and appear to play a
major role in smooth muscle contraction in
the gastrointestinal and genitourinary
tracts and to mediate salivation.
 Although M3 receptors are found at
modest densities in many areas of the
CNS, no central role has been elucidated

111. M4
 M4 receptors are expressed in the
hippocampus, cortex, striatum, thalamus,
and cerebellum
 Striatal M4 receptors may oppose the
effects of D1 dopamine receptors and have
been implicated as putative targets for
anticholinergics used as antiparkinsonian
agents—although other muscarinic
receptor subtypes may also be involved

112. M5
 M5 receptors are expressed in various
peripheral and cerebral blood vessels and
comprise a very small percentage of
muscarinic receptors in the brain
 They may mediate cholinergic cerebral
arterial vasodilation.

113. Nicotinic Receptors
 Nicotinic acetylcholine receptors, like 5-
HT3 receptors, are members of the ligand-
gated ion channel superfamily and mediate
rapid, excitatory signaling
 Nicotinic acetylcholine receptor subunits
are heterogeneous and associate in varied
combinations

114.  These various nicotinic acetylcholine
receptor subunits can be categorized into
three general functional classes:
(1) skeletal muscle subunits (α1, β1, δ and ε),
(2) Standard neuronal subunits (α2–α6 and
β2–β4), and
(3) Subunits capable of forming homomeric
receptors (α7–α9).

115.  In the periphery, nicotinic acetylcholine
receptors are found in skeletal muscle,
autonomic ganglia, and the adrenal
medulla
 In the brain, they are found in many
locations including the neocortex,
hippocampus, thalamus, striatum,
hypothalamus, cerebellum,
substantia nigra, ventral tegmental
area, and dorsal raphe nucleus

116.  Most nicotinic acetylcholine receptors in
mammalian brain contain either α4β2 or α7
subunit combinations
 They frequently appear to mediate
presynaptic enhancement of
neurotransmitter release, influencing the
release of acetylcholine, dopamine,
norepinephrine, serotonin, as well as
GABA and glutamate

117.  Nicotinic receptors have been implicated
in cognitive function, especially working
memory, attention, and processing speed
 Cortical and hippocampal nicotinic
acetylcholine receptors appear to be
significantly decreased in Alzheimer's
disease, and nicotine administration
improves attention deficits in some
patients
 The acetyl cholinesterase inhibitor
galantamine used in the treatment of
Alzheimer's disease also acts to positively

118.  The α7 nicotinic acetylcholine receptor
subtype has been implicated as one of
many possible susceptibility genes for
schizophrenia, with lower levels of this
receptor being associated with impaired
sensory gating
 Some rare forms of the familial epilepsy
syndrome autosomal dominant nocturnal
frontal lobe epilepsy (ADNFLE) are
associated with mutations in the α4 or β2
subunits of the nicotinic acetylcholine
receptor

119.  Finally, the reinforcing properties of
tobacco use are proposed to involve the
stimulation of nicotinic acetylcholine
receptors located in mesolimbic
dopaminergic reward pathways

120. Acetylcholine and Drugs
 The most common use of anticholinergic drugs in
psychiatry is in treatment of the motor
abnormalities caused by the use of classic
antipsychotic drugs (e.g., haloperidol).
 The efficacy of the drugs for that indication is
determined by the balance between acetylcholine
activity and dopamine activity in the basal
ganglia.

121.  In healthy people, the activity of the
nigrostriatal dopamine pathway is partially
balanced by the activity of cholinergic
pathways in the basal ganglia.
 Blockade of D2 receptors in the striatum
upsets this balance, but the balance can
be partially restored, albeit at a lower set
point, by antagonism of muscarinic
receptors

122. Blockade of those receptors leads to the
commonly seen adverse effects of blurred vision,
dry mouth, constipation, and difficulty in initiating
urination.
Excessive blockade of CNS cholinergic
receptors causes confusion and delirium.
Drugs that increase cholinergic activity by
blocking breakdown by acetyl cholinesterase
(e.g., donepezil ) have been shown to be effective
in the treatment of dementia of the Alzheimer's
type

123. Acetylcholine and
Psychopathology
 The most common association with
acetylcholine is dementia of the Alzheimer's
type and other dementias
 Acetylcholine may also be involved in mood and
sleep disorders.

124. CONCLUSION
 Neurotransmission is the communication
b/w genomes of two neurons, through
signal transduction cascade, leading to
gene activation & biological response.
 Understanding neurotransmitters, their
receptor partners & other near/distant
relations (transporters & transduction), is
essential for our approaches to define &
treat psychiatric disorders.

125. •Exploring the physiological & genetic basis of
neurotransmitter function may pave the way in
understanding psychopathology & nosology.
•Future researches clearly have potential to
further advance our knowledge in areas of
psychopathology, pharmacotherapy &
pharmacogenomics.

126. REFERENCES
1. KAPLAN AND SADDOCK’S COMPREHENSIVE TEXTBOOK OF
PSYCHIATRY. 9th ed.
2. STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY:
NEUROSCIENTIFIC BASIS AND PRACTICAL APPLICATIONS. 4th ed.
3. GUYTON & HALL PHYSIOLOGY 12th ed.
4. NEUROSCIENCE ONLINE LECTURE BY Jack C. Waymire, Ph.D.,
Department of Neurobiology and Anatomy, The UT Medical School at
Houston
5. KAPLAN & SADDOCKS SYNOPSIS OF PSYCHIATRY 10th ed.