DR PRASHANT MISHRA

1. PRESENTATOR: DR PRASHANT MISHRA
MODERATOR : PROF. V.SHARBANDHRAJ

2. Neurotransmitters
• Neurotransmitters are endogenous chemicals that
transmit signals from a neuron to a target cell across a
synapse.
• Neurotransmitters are packaged into synaptic
vesicles clustered beneath the membrane on the presynaptic
side of a synapse, and are released into the synaptic cleft,
where they bind to receptors in the membrane on the
postsynaptic side of the synapse.
• Release of neurotransmitters usually follows arrival of an
action potential at the synapse, but may also follow graded
electrical potentials.

3. Types of neurotransmitters
• Major neurotransmitters
 Amino acids:
 glutamate, aspartate, D-serine, γ-aminobutyric acid
(GABA), glycine
 Monoamines and other biogenic amines:
 dopamine (DA), norepinephrine, epinephrine ,histamine,
serotonin (5-HT)
 Others:
 acetylcholine (ACh), adenosine, anandamide, nitric oxide,
etc.

4. Dopamine
• Dopamine neurons are more widely distributed than those of
other monamines, residing in the midbrain substantia
nigra and ventral tegmental area and in the
periaqueductal gray, hypothalamus, olfactory bulb, and
retina.
• In the periphery, dopamine is found in the kidney where it
functions to produce renal vasodilation, diuresis, and
natriuresis.
• Three dopamine systems are highly relevant to psychiatry:
The nigrostriatal, mesocorticolimbic, and
tuberohypophyseal system.

5. Tyrosine, a precursor to dopamine, is taken up into dopamine nerve terminals
via a tyrosine transporter and converted into DOPA by the enzyme tyrosine
hydroxylase (TOH). DOPA is then converted into dopamine (DA) by the
enzyme DOPA decarboxylase (DDC). After synthesis, dopamine is packaged
into synaptic vesicles via the vesicular monoamine transporter (VMAT2) and
stored there until its release into the synapse during neurotransmission.

6. Degradation
• Two enzymes that play major roles in the degradation of dopamine are
monoamine oxidase and catechol O-methyltransferase (COMT).
• MAO is located on the outer membrane of mitochondria.
• Two MAO isozymes
 MAO-A : Which preferentially deaminates serotonin and norepinephrine.
 MAO-B : Which deaminates dopamine, histamine, and a broad spectrum of
phenylethylamines.
 COMT is located in the cytoplasm and is widely distributed throughout
the brain and peripheral tissues.
 It has a wide substrate specificity, catalyzing the transfer of methyl
groups from S-adenosyl methionine to the m-hydroxyl group of
most catechol compounds.
 The predominant metabolites of dopamine is Homovanillic acid
(HVA)

8. Storage
 Dopamine synthesized within neurons from common amino
acid precursors (step 1) and taken up into synaptic vesicles via
a vesicular monoamine transporter (step 2).
 Upon stimulation, vesicles within nerve terminals fuse with
the presynaptic terminal and release the neurotransmitter into
the synaptic cleft (step 3).
 Once released, the monoamines interact with postsynaptic
receptors to alter the function of postsynaptic cells (step 4),
and they may also act on presynaptic autoreceptors on the
nerve terminal to suppress further release (step 5).
 In addition, released dopamine may be taken back up from the
synaptic cleft into the nerve terminal by DAT Dopamine
Transpoter(step 6), a process known as reuptake.
 Once monoamines are taken up, they may be subject to
enzymatic degradation (step 7), or they may be protected from
degradation by uptake into vesicles.

9. receptors Adenyl cyclase = produce cyclic AMP

10. Dopamine transporter (DAT) exists presynaptically and is responsible for clearing excess
dopamine out of the synapse. The vesicular monoamine transporter (VMAT2) takes
dopamine up into synaptic vesicles for future neurotransmission. There is also a
presynaptic dopamine-2 autoreceptor, which regulates release of dopamine from the
presynaptic neuron. In addition, there are several postsynaptic receptors. These include
dopamine-1, dopamine-2, dopamine-3, dopamine-4, and dopamine-5 receptors. The
functions of the dopamine-2 receptors are best understood, because this is the primary
binding site for virtually all antipsychotic agents as well as for dopamine agonists used to
treat Parkinson's disease.

11. Presynaptic dopamine-2 autoreceptors are "gatekeepers" for dopamine. That is,
when these gatekeeping receptors are not bound by dopamine (no dopamine in
the gatekeeper's hand), they open a molecular gate, allowing dopamine release
(A). However, when dopamine binds to the gatekeeping receptors (now the
gatekeeper has dopamine in his hand), they close the molecular gate and
prevent dopamine from being released (B).

12. Tracts in brain…
 The Mesolimbic Dopamine Pathway : midbrain ventral tegmental area to the
nucleus accumbens .a part of the limbic system of the brain thought to be involved in
many behaviors such as pleasurable sensations, the powerful euphoria of drugs of
abuse, as well as delusions and hallucinations of psychosis.
 The Mesocortical Dopamine Pathway : It also projects from the midbrain
ventral tegmental area but sends its axons to areas of the prefrontal cortex, where
they may have a role in mediating cognitive symptoms (dorsolateral prefrontal
cortex) and affective symptoms (ventromedial prefrontal cortex) of schizophrenia.
 The Nigrostriatal Dopamine Pathway : which projects from the substantia
nigra to the basal ganglia or striatum, is part of the extrapyramidal nervous system
and controls motor function and movement.
 Tuberoinfundibular Dopamine Pathway : projects from the hypothalamus to
the anterior pituitary gland and controls prolactin secretion.
 The fifth dopamine pathway arises from multiple sites, including the
periaqueductal gray, ventral mesencephalon, hypothalamic nuclei, and lateral
parabrachial nucleus, and it projects to the thalamus. Its function is not
currently well known.

13. The mesolimbic dopamine pathway, which projects from the ventral tegmental
area in the brainstem to the nucleus accumbens in the ventral striatum (A), is
involved in regulation of emotional behaviors and is believed to be the
predominant pathway regulating positive symptoms of psychosis. Specifically,
hyperactivity of this pathway is believed to account for delusions and

14. ventral tegmental area to the prefrontal cortex .(DLPFC) are believed to be
involved in the negative and cognitive symptoms of schizophrenia

15. Mesocortical dopamine projections specifically to the ventromedial prefrontal
cortex (VMPFC) are believed to mediate negative and affective symptoms
associated with schizophrenia.

16. projects from the substantia nigra
to the basal ganglia or striatum. It
is part of the extrapyramidal
nervous system and plays a key
role in regulating movements.
When dopamine is deficient, it
can cause parkinsonism with
tremor, rigidity, and
akinesia/bradykinesia. When DA
is in excess, it can cause
hyperkinetic movements like tics
and dyskinesias. In untreated
schizophrenia, activation of this
pathway is believed to be
"normal."

17. from hypothalamus to
anterior pituitary
regulates prolactin
secretion into the
circulation. Dopamine
inhibits prolactin
secretion. In untreated
schizophrenia,
activation of this
pathway is believed to
be "normal."

18. Thalamic dopamine pathway
It arises from multiple sites, including the
periaqueductal gray matter, ventral mesencephalon,
various hypothalamic nuclei, and lateral parabrachial
nucleus.
It may be involved in sleep and arousal mechanisms by
gating information passing through the thalamus to the
cortex and other brain areas.
There is no evidence at this point for abnormal
functioning of this dopamine pathway in schizophrenia.

19. Disorders associated with
dopaminergic system…
 Parkinsonism : Decrease Dopamine.
 It occurs in substantia nigra
 Leading to symptoms like
 rigidity ,
 bradykinesia and
 tremors

20. Substance Abuse
 Substance Abuse :
 Nucleus Accumbens is a center for reward.
 Occurs due to increased release of dopamine caused
by the psychotropic substances like
 morphin
 heroin
 Cannabis
 cocaine
 nicotine

21. REWARD PATHWAY

22. Schizophrenia
 Schizophrenia :
 Increase And Decrease Of Dopamine
 In Different Region Of Brain.
 Mesolimbic pathways
 Mesocortical pathways

23.  Depression :
 Decrease Of Dopamine in following areas
 VMPFC- Depressed mood
 PFC, Hypothalamus, Nucleus Accumbens - Apathy
 Nucleus Accumbens Striatum Hypothalamus- Fatigue
 DLPFC- Executive Dysfunction
 Nucleus Accumbens ,PFC – Psychomotor
Agitation/Retardation

24.  ADHD :
 Decrease In Dopamine Level in anterior frontal cortex
 An area associated with cognitive function such as
 attention
 concentration.
 Impulse Control Disorder :
 Decrease In Dopamine Level.

25. DRUGS AFFECTING
DOPAMINERGIC SYSTEM…
 Dopamine Agonist:
 Levodopa
 Carbidopa
 Ropinirole
 Antidepressent:
 Bupuropion
 Antipsychotics:
 Typical antipsychotic like halopoperidol, pimozide,
 Atypical antipsychotics like olanzapine, quetiapine,
resperidone etc
 Stimulants:
 Methylphenidate
 Modafinil
 Armodafinil

26. Reference
 Kaplan & Sadock's Comprehensive Textbook of
Psychiatry
 Stahl's essential psychopharmacology
 Internet

27. THANK YOU