Monoamine Neurotransmitters & its Psychiatry corelevance

1. Presenter : Dr. Nimish Savaliya
Moderator : Prof. Dr. Dinesh Singh Rathor
ROLE OF NEUROTRANSMITTERS IN PSYCHIATRY :
BIOGENIC MONOAMINE NEUROTRANSMITTERS

2. Contents Of Seminar :
 Introduction
 Criteria for Neurotransmitters
 Types of Neurotransmitters :
1. Dopamine
2. Serotonin
3. Histamine
4. Acetylcholine
5. Epinephrine & Norepinephrine
 Synthesis & Degradation of different types of neurotransmitters
 Receptor & it’s location
 Clinical implications

3.  Neurotransmitter :- Defined as a chemical messenger that
carries, boosts, and balances signals between neurons , or nerve
cells, and other cells in the body.
 They are released from presynaptic nerve terminals into the
synaptic cleft.
 Affect a wide variety of both physical and psychological functions
including heart rate, sleep, appetite, mood and fear
 Enable neurotransmission
DEFINITION

4. Criteria:- To be met for Neurotransmitter
 It is synthesised by a neuron.
 It is present in the presynaptic terminal and is released in amounts
sufficient to exert a defined action on a postsynaptic neuron or effector
organ
 Substance must be released in response to presynaptic depolarisation
which must occur in calcium dependent manner.
 Specific receptor for the substance must be present on postsynaptic cell.

6. Synthesised from precursors under the influence of enzymes
Stored in vesicles
Action potential arrives at axon terminal
Voltage gated calcium channels open and calcium enters the cell
Fusion of synaptic vesicles with presynaptic membrane
Exocytosis occurs
Release of neurotransmitter

7. Exocytosis
Binding with
postsynaptic
receptors
Deactivation
either by
reuptake or
enzymatic
degradation

8. Types of neurotransmitters
Monoamine
neurotransmitter
Amino acid
neurotransmitters
Novel neurotransmitters
● Dopamine
● Epinephrine
● Norepinephrine
● Serotonin
● Histamine
● Acetylcholine
● Glutamate
● GABA
● Endocannabinoids
● Nitric oxide
● Carbon monoxide
● Hydrogen sulphide
● D serine

9. Properties of some major neurotransmitters
Neurotransmitters Postsynaptic cleft Precursors
Ach (Acetylcholine) Excitatory Choline + Acetyl
CoA
Glutamate Excitatory Glutamine
GABA Inhibitory Glutamate
Glycine Inhibitory Serine
Catecholamines
• Epinephrine
• Norepinephrine
• Dopamime
Excitatory
Excitatory
Both Excitatory and
Inhibitory
Tyrosine
Serotonin (5-HT) Inhibitory(mostly)
Excitatory
Tryptophan
Histamine Excitatory Histidine
ATP Excitatory ADP
Neuropeptides Excitatory and
Inhibitory
Amino acids
A. Small molecules
B. Large molecules
• Neuropeptides
(Substance P,
Endorphins,
Insulin, Glucagon
etc)

10. 1. DOPAMINE
2. SEROTONIN
3. HISTAMINE
4. ACETYLCHOLINE
5. EPINEPHRINE & NOREPINEPHRINE
MONO-AMINE NEUROTRANSMITTERS :

11.  3,4 DIHYROXYPHENETHYLAMINE
 High concentration in :
1. Corpus striatum
2. Limbic system
3. Hypothalamus
4. Frontal cortex
1. DOPAMINE

12. TYROSINE
LEVODOPA
DOPAMINE
 SYNTHESIS :
Tyrosine hydroxylase
Amino acid
decarboxylase

15.  Once synthesized, dopamine is released into synaptic
clefts.
 Further on; 2 routes-
 Reuptake into synaptic vesicle and reuse as a
neurotransmitter
 Metabolism by MAO and COMT enzymes ; with eventual
formation of Homovanillic acid (HVA)

17. Dopamine receptors :
Receptor
subtype
D1 D2 D3 D4 D5
Gprotein Gs Gi Gi Gi Gs
Localization • Caudate
• Putamen
• Nucleus
accumbens
• Caudate
• Putamen
• NA
Nucleus
accumbens
• Frontal
cortex
• Midbrain
• Amygdala
• Hippocampus
• Hypothalamus
Action • Locomotion
• Reward
• Reinforcement
• Learning
• Memory
• Locomotion
• Reward
• Reinforcement
• Learning
• Locomotion
• Role in
cognition &
emotion
- • Learning and
memory

22.  Dopamine which is present in Substantia nigra needed for
overall facilitation of movements.
 Via two path ways: Dopamine
(via D1 receptors) (via D2 receptors)
Activates Direct pathway Activates Indirect pathway
Facilitation Inhibition
Role of Dopamine :

23. 1. MESOLIMBIC- VTA to ventral striatum
2. MESOCORTICAL- Ventral tegmental area to cerebral cortex
3. NIGROSTRIATAL – Substantia nigra to dorsal striatum
4. TUBEROHYPOPHYSEAL- Hypothalamic Arcuate And
Paraventricular Nuclei to Pituitary Gland
5. MESOACCUMBENS PATHWAY
DOPAMINERGIC PATHWAYS

24.  Central element in the neural representation of reward.
 Plastic changes in this pathway are thought to underlie drug
addiction.
 Dopamine reuptake transport pumps are few in prefrontal cortex
unlike other brain areas. So dopamine acts in prefrontal cortex via
volume neurotransmission.
 Volume neurotransmission is neurotransmission without synapse .
AKA Non synaptic Diffusion neurotransmission.
 Dopamine is free to spill over from that synapse and diffuse to
neighbouring dopamine receptor to stimulate them.
MESOACCUMBENS PATHWAY

26. Clinical Implications

27. SCHIZOPHRENIA

35. DRUG ADDICTION :
 Acute drug administration :
1. Increased DA release
2. Inhibit reuptake
3. Act as DA agonist
 Release supraphysiological doses of DA
 NUCLEUS ACCUMBENS-
REINFORCEMENT
 AMYDALA AND HIPPOCAMPUS –
CRAVINGS

36. COCAINE ADDICTION :
 Cocaine causes pleasurable feelings that motivate drug use by sharply
elevating dopamine concentrations in the synapses of the reward
system.
 Cocaine raises synaptic dopamine levels by preventing dopamine
transporters from removing dopamine from the synapse and by
stimulating dopamine-releasing neurons to release dopamine that they
normally hold in reserve.
 Cocaine-induced increases in dopamine signaling promote repeated
cocaine use by increasing the activity of dopamine type D1 receptors
in a circuit that supports the conversion of urges into action, while
suppressing the activity of dopamine type D2 receptors in an opposing
circuit, and by increasing the activity of dopamine type D3 receptors.

37. ADHD :

38. RECENT ADVANCES :
 EATING DISORDERS – DOPAMINE DECREASES FEEDING
 ANTI – INSULIN
 ANALGESIC
 ROLE IN APOPTOSIS
 MEMORY
 IMMUNE SYSTEM

39.  5- HYDROXY TRYPTAMINE
 Highest concentration in platelets and GIT (enterochromaffin cells
and myenteric plexus)
 FROM - Caudal and rostral raphe nuclei
 TO - Amygdala , Cingulate gyrus , Striatum , Hippocampus ,
Thalamus
2. SEROTONIN

40. TYROSINE
5 - Hydroxy L- Tryptophan
Serotonin(5-HT)
SYNTHESIS :
Tryptophan hydroxylase
Amino acid
decarboxylase

44. Receptors Location and Actions
 5-HT1
5-HT1A, 5-HT1B, 5-
HT1D, 5-HT1E, 5-
HT1F, 5-HT1P
Brain, Raphe nuclei
 5-HT2
5-HT2A
5-HT2B
5-HT2C
Platelet aggregation and smooth
muscle contraction
 5-HT3 Gastrointestinal tract, area
postrema; vomiting
 5-HT4 Gastrointestinal tract; brain;
secretion and peristalsis
 5-HT5A,B Brain;
 5-HT6,7 Brain; 5-HT6 high affinity for
antidepressant drugs

45. SUBTYPES FUNCTION
5HT1A Antidepressent,Increases dopamine
release;Anxiolytic
5HT1B ,1D,1E,1F Antimigraine
5HT2A Antipsychotic.Decreases dopamine release
5HT2B Regulation of stomach contraction
5HT2C Linked to appetite,anxiety,seizures
And antipsychotic action
5HT3 Antiemetic,Anxiolytic,Cognitive
enhancement
5HT4 Anxiety and cognition
RECEPTORS :

46. RECEPTOR FUNCTION
5HT6 Target site for hallucinogens
Target site for antipsychotics
5HT7 Regulation of circadian rhythm.

47. Clinical Implications

48.  5 HT1A antagonism - improvement of positive symptoms.
1. Decrease glutamate release
2. Decreases dopamine release.
 Release of dopamine via inactivation of 5HT2A receptors in the
meso-cortical area prevents occurrence of negative symptoms.
SCHIZOPHRENIA :

49. SYMPTOM AREA INVOLVED NEUROTRANSMITTER
Depressed mood Amygdala and ventromedial
prefrontal cortex
Serotonin, Nor- epinephrine
,and Dopamine
Sleep disturbance Hypothalamus, Thalamus
,Forebrain ,Prefrontal cortex
Serotonin, Nor- epinephrine
,and Dopamine
Psychomotor changes Cerebellum,
Nucleus accumbens
Serotonin, Nor-epinephrine,
Dopamine
Weight and appetite changes Hypothalamus Serotonin
Suicidality Amygdala,Ventromedial
prefrontal cortex, Orbitofrontal
cortex
Serotonin
Guilt Amygdala,Ventromedial
prefrontal cortex.
Serotonin
Apathy Prefrontal cortex,
Hypothalamus,Nucleus
accumbens
Norepinephrine,Dopamine
DEPRESSION :

50. SYMPTOM AREA NEUROTRANSMIITER
Elevated/irritable mood Amygdala, Orbitofrontal
cortex,Ventromedial prefrontal
cortex
Serotonin,nor-epinephrine,and
dopamine
Grandiosity
Pressured speech
Flight of ideas
Nucleus accumbens Serotonin,nor-epinephrine,and
dopamine
Inflated self esteem
Increased risk taking
Orbitofrontal cortex
Prefrontal cortex
Serotonin,nor-epinephrine,and
dopamine
Decreased need for sleep Thalamus ,Hypothalamus,
Basal forebrain
Serotonin,nor-epinephrine,and
dopamine
Distractibilty Dorsolateral prefrontal cortex Norepinephrine and dopamine.
Increased goal directed activity Corpus straitum Serotonin ,Dopamine
Mania :

51.  Increased 5HT2A receptors in caudate nucleus
 Increased activations in the cortico-striato-thalamo-cortical
circuit, particularly in the caudate, putamen, anterior
thalamus, orbitofrontal cortex, amygdala, and brain stem.
Obsessive Compulsive Disorder :

52. OTHER DISORDERS :
 Serotonin is a neurotransmitter primarily associated with hallucinogenic
drugs like MDMA or ecstasy, LSD, psilopsybin mushrooms, philosophers
stones.
 Affects sexual desire and sleep during active drug use, but upon cessation
can cause significant disruptions in the normal healthy functioning of both.
 Eating disorders – lower CSF levels of serotonin
 ANXIETY
 AGEING
 ADHD
 MIGRAINE

53. Role of Serotonin in Migraine :
 Levels of serotonin in a person's system
may rise and suddenly fall prior to migraine
 Low levels of serotonin are linked to
 both migraine and depression
 5-HT concentrations in blood has been found
to increase during the prodromal (aura)
phase and subsequently, decrease to
subnormal levels in the headache phase

57.  Originate from the tubero-mamillary nucleus of the posterior
hypothalamus and send projections to most parts of the brain.
 Arousal, control of pituitary hormone secretion, suppression of eating
and cognitive functions.
 G-protein-coupled H1-H4 receptors.
 Wake-promoting substance - treat sleep-wake disorders, especially
narcolepsy, via modulation of H3 receptor function.
 Involved in the pain perception.
3. HISTAMINE :

58. HISTIDINE
HISTAMINE
STORED IN MAST CELLS
SYNTHESIS :
Histidine decarboxylase

61. SUBTYPE ACTION
H1 Antagonism produces sedation and weight
gain
H2 Antagonism is useful in management of
peptic ulcer
H3 Antagonism leads to arousal and appetite
suppression
RECEPTORS :

62. PSYCHIATRIC DISORDERS :
Low levels
1. Alzheimer disease.
2. Seizures .
3. Convulsions.
High levels
1. Parkinson’s disease.
2. Schizophrenia.
3. Ischaemic brain injury

63.  The central histamine system is involved in many brain functions such as
arousal, control of pituitary hormone secretion, suppression of eating and
cognitive functions.
 Its role in wake-promoting substance to treat sleep-wake disorders,
especially narcolepsy
 Brain histamine levels are decreased in Alzheimer's disease.
 High histamine concentrations are found in the brains of Parkinson's
disease and schizophrenic patients.
 Low histamine levels are associated with convulsions and seizures.
Clinical Implications :

64.  Acetylcholine was the first neurotransmitter discovered and it
was originally described as vagus puff because of its ability to
mimic the electrical stimulation of the vagus nerve.
 It is now known to be a neurotransmitter at all autonomic
ganglia, at the neuromuscular junction and at many synapses in
the CNS.
ACETYLCHOLINE

65. ACETYLCHOLINE
 In the brain, acetylcholine functions as a neurotransmitter and as
a neuromodulator.
 Important role in arousal, attention, memory and motivation.
Acetylcholine
 CNS - cholinergic projections from the basal forebrain to the
cerebral cortex and hippocampus support the cognitive functions
of those target areas
 PNS - activates muscles and is a major neurotransmitter in the
autonomic nervous system.

66. Acetyl coA + choline
Acetylcholine
SYNTHESIS
Choline acetyltransferase

72.  In CNS Ach is found primarily in interneurons.
 Many cholinergic pathways have been identified.
 The most important is the cholinergic projection from the NUCLEUS
OF BASALIS MEYNERT (in the basal forebrain) to the forebrain
neocortex and associated limbic structures.

73.  Degeneration of this pathway is one of the pathologies associated
with ALZHEIMER’S DISEASE.
 Degeneration of this pathway is one of the pathologies associated
with ALZHEIMER’S DISEASE.
 Therefore , drugs that promote acetylcholine signaling are
beneficial.

74.  The Mesopontine Complex – consists of cholingeric neurons within
pedunculopontine and tegmetal nuclei which provide innervation to
thalamus and brainstem regions such as LC.
 Modulation of Cholinergic INTERNEURONS of STRIATUM has
been implicated in the antiparkinsonian actions of anticholinergic
agents.

75. RECEPTORS :
1.
M1 - Linked to cognition and seizures
2.
M2 - Regulation of cardiac function
3.
M3 - Regulation of smooth muscle contraction
4.
M4 & M5 – Anti-parkinsonism
5.
Nicotinic - Addiction, seizures , cognitive enhancement

77. IMPLICATIONS IN TREATMENT
 Anticholinergics for management of antipsychotic induced EPS
 Donepezil in dementia ; acting via inhibition of cholinesterase

78. PSYCHIATRIC DISORDERS :
 Cholinergic deficits in basal forebrain structures and their projections in
schizophrenia - cognitive dysfunction
 Functional roles in conscious awareness, and components of information
processing, including attention, working memory, encoding, memory
consolidation, and retrieval.
 Dopamine binding to D2 receptors decreases acetylcholine release.
 Antipsychotics inhibit dopamine.
 Excess binding of acetylcholine to D2 receptors Leading to EPS.
 Anticholinergic agents - Leading to decrease in EPS.
 Linked to Alzheimer disease – Progressive loss of cholinergic neurons
(Cholinesterase inhibitors beneficial in management )

79.  From - Locus cerulus , lateral tegmental noradrenergic nuclei
 To – neocortex , Thalamus , Hippocampus and midbrain tectum
5. EPINEPHRINE AND NOR-EPINEPHRINE

80. Dopamine
Nor - Epinephrine
Epinephrine
Synthesis :
Dopamine β hydroxylase
Phenylethanolamine N
methyltransferase

84. SUBTYPES ACTIONS
α1A,B,D Antagonists act as antihypertensives
α2A,B,C Antagonists act as sedatives and
antihypertensives
β1 Linked to cardiac function
β2 Regulation of bronchial muscle contraction
β3 Regulation of adipose tissue function
RECEPTORS

85. PSYCHIATRIC DISORDERS :
 Linked to features of anxiety
 Via connections-
1. Hypothalamus to amygdala- Fear response.
2. Parabrachial nucleus to amygdala- Asthma like features.
3. Periaqueductal gray mater to amygdala- Avoidance.

86.  Monoamine hypothesis of Depression postulates deficiency of
serotonin and norepinephrine neurotransmission in the brain.
 Currently available antidepressants act on one or more mechanism
compatible with the monoamine hypothesis which include inhibition
of re-uptake of serotonin or norepinephrine and antagonism of
presynaptic inhibitory norepinephrine or serotonin receptors.
Clinical Implication :

87.  Reduced NE neurotransmission is associated with decreased
alertness, low energy, problems of inattention, concentration and
cognitive ability.
 NE plays a determinant role in executive functioning regulating
cognition, motivation , and intellect, which are fundamental in social
relationships.
 Social dysfunction is possibly one of the most important factors
affecting the quality of life in depressed patients.

88. ADHD :

89. NEUROTRANSMITTERS IN ANXIETY SPECTRUM DISORDERS :

90. IMPLICATION IN TREATMENT :
 SNRIs :
 Tend to increase their levels by preventing reuptake
 Leading to amelioration of symptoms.
 TCAs , Venlafaxine , Mirtazapine , Bupropion - Block reuptake
of nor-epinephrine.
 MAO Inhibitors - Blocks catabolism of nor-epinephrine.
 Clonidine and metoprolol also act via this route.
 Propanolol acts via α2 receptors to decrease lithium induced
tremors

91. IMPLICATION IN TREATMENT :
 TCAs, SNRIs, Cocaine : Increase levels of NE in the
synapse that leads to the antidepressant action.
 Metyrosine, Reserpine, Tetrabenazine, Deutetrabenazine,
Valbenazine : Decrease levels of NE that leads to
Depression, hypotension & also leads to decrease in levels
of DA that leads to parkinsonism like features

92. NON – PSYCHIATRIC USES OF NEUROTRANSMITTERS :
 SEROTONIN
1. Anti-emetic
2. Anti- migraine
 DOPAMINE
1. Cardiac arrest
2. Hypotension
 NOR-EPINEPHRINE
1. Glaucoma
2. Migraine
3. Hypertension
4. Benign prostatic hypertrophy.
 HISTAMINE
1. Sexual dysfuction.
2. Sleep-rhythm disorders.
 ACETYLCHOLINE
1. Myasthenia gravis.
 EPINEPHRINE
1. Anaphylactic reaction
2. Asthma.
3. Superficial bleeding.

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References :

95. Thank you