dopamine-120904235349-phpapp01.ppt

8/14/2019 dopamine-120904235349-phpapp01.ppt

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PRESENTATOR: DR PRASHANT MISHRA

MODERATOR : PROF. V.SHARBANDHRAJ


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Neurotransmitters Neurotransmitters are endogenous chemicals thattransmit signals from a neuron to a target cellacross asynapse.

Neurotransmitters are packaged into synapticvesiclesclustered beneath the membrane on the presynapticside 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 anaction potential at the synapse, but may also follow gradedelectrical potentials.
http://en.wikipedia.org/wiki/Endogenoushttp://en.wikipedia.org/wiki/Chemistryhttp://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Synapsehttp://en.wikipedia.org/wiki/Synaptic_vesicleshttp://en.wikipedia.org/wiki/Synaptic_vesicleshttp://en.wikipedia.org/wiki/Synaptic_clefthttp://en.wikipedia.org/wiki/Action_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Membrane_potentialhttp://en.wikipedia.org/wiki/Action_potentialhttp://en.wikipedia.org/wiki/Action_potentialhttp://en.wikipedia.org/wiki/Action_potentialhttp://en.wikipedia.org/wiki/Synaptic_clefthttp://en.wikipedia.org/wiki/Synaptic_clefthttp://en.wikipedia.org/wiki/Synaptic_clefthttp://en.wikipedia.org/wiki/Synaptic_vesicleshttp://en.wikipedia.org/wiki/Synaptic_vesicleshttp://en.wikipedia.org/wiki/Synaptic_vesicleshttp://en.wikipedia.org/wiki/Synapsehttp://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Neuronhttp://en.wikipedia.org/wiki/Chemistryhttp://en.wikipedia.org/wiki/Endogenous


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Types of neurotransmitters

Major neurotransmitters Amino acids:

glutamate, aspartate, D-serine, -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.


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Dopamine

Dopamine neurons are more widely distributed than those ofother monamines, residing in the midbrain substantianigra and ventral tegmental area and in theperiaqueductal gray, hypothalamus, olfactory bulb, and

retina. In the periphery, dopamine is found in the kidneywhere it

functions to produce renal vasodilation, diuresis, andnatriuresis.

Three dopamine systems are highly relevant to psychiatry:The nigrostriatal, mesocorticolimbic, andtuberohypophysealsystem.


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Tyrosine, a precursor to dopamine, is taken up into dopamine nerve terminalsvia a tyrosine transporter and converted into DOPA by the enzyme tyrosinehydroxylase (TOH). DOPA is then converted into dopamine (DA) by theenzyme DOPA decarboxylase (DDC). After synthesis, dopamine is packaged

into synaptic vesicles via the vesicular monoamine transporter (VMAT2) andstored there until its release into the synapse during neurotransmission.


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Degradation

Two enzymes that play major roles in the degradation of dopamine aremonoamine 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 throughoutthe brain and peripheral tissues.

It has a wide substrate specificity, catalyzing the transfer of methylgroups from S-adenosyl methionine to the m-hydroxyl group ofmost catechol compounds.

The predominant metabolites of dopamine is Homovanillic acid(HVA)


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Storage

Dopamine synthesized within neurons from common aminoacid precursors (step 1) and taken up into synaptic vesicles viaa vesicular monoamine transporter (step 2).

Upon stimulation, vesicles within nerve terminals fuse withthe 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 thenerve terminal to suppress further release (step 5).

In addition, released dopamine may be taken back up from thesynaptic cleft into the nerve terminal by DAT DopamineTranspoter(step 6), a process known as reuptake.

Once monoamines are taken up, they may be subject toenzymatic degradation (step 7), or they may be protected from

degradation by uptake into vesicles.


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receptorsAdenyl cyclase = produce cyclic AMP


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Dopamine transporter (DAT) exists presynaptically and is responsible for clearing excessdopamine out of the synapse. The vesicular monoamine transporter (VMAT2) takesdopamine up into synaptic vesicles for future neurotransmission. There is also apresynaptic dopamine-2 autoreceptor, which regulates release of dopamine from thepresynaptic neuron. In addition, there are several postsynaptic receptors. These includedopamine-1, dopamine-2, dopamine-3, dopamine-4, and dopamine-5 receptors. Thefunctions 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 totreat Parkinson's disease.


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Presynaptic dopamine-2 autoreceptors are "gatekeepers" for dopamine. That is,when these gatekeeping receptors are not bound by dopamine (no dopamine inthe 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 andprevent dopamine from being released (B).


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Tracts in brain

The Mesolimbic Dopamine Pathway : midbrain ventral tegmental area to thenucleus accumbens .a part of the limbic system of the brain thought to be involved inmany behaviors such as pleasurable sensations, the powerful euphoria of drugs ofabuse, as well as delusions and hallucinations of psychosis.

The Mesocortical Dopamine Pathway : It also projects from the midbrainventral tegmental area but sends its axons to areas of the prefrontal cortex, where

they may have a role in mediating cognitive symptoms (dorsolateral prefrontalcortex) and affective symptoms (ventromedial prefrontal cortex) of schizophrenia.

The Nigrostriatal Dopamine Pathway : which projects from the substantianigra to the basal ganglia or striatum, is part of the extrapyramidal nervous systemand controls motor function and movement.

Tuberoinfundibular Dopamine Pathway : projects from the hypothalamus tothe anterior pituitary gland and controls prolactin secretion.

The fifth dopamine pathway arises from multiple sites, including theperiaqueductal gray, ventral mesencephalon, hypothalamic nuclei, and lateralparabrachial nucleus, and it projects to the thalamus. Its function is notcurrently well known.


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The mesolimbic dopamine pathway, which projects from the ventral tegmentalarea in the brainstem to the nucleus accumbens in the ventral striatum (A), isinvolved 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


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


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Mesocortical dopamine projections specifically to the ventromedial prefrontalcortex (VMPFC) are believed to mediate negative and affective symptomsassociated with schizophrenia.


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projects from the substantia nigrato the basal ganglia or striatum. Itis part of the extrapyramidalnervous system and plays a keyrole in regulating movements.

When dopamine is deficient, itcan cause parkinsonism withtremor, rigidity, andakinesia/bradykinesia. When DAis in excess, it can causehyperkinetic movements like tics

and dyskinesias. In untreatedschizophrenia, activation of thispathway is believed to be"normal."


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from hypothalamus toanterior pituitaryregulates prolactinsecretion into thecirculation. Dopamineinhibits prolactinsecretion. In untreatedschizophrenia,

activation of thispathway is believed tobe "normal."


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Thalamic dopamine pathwayIt arises from multiple sites, including theperiaqueductal gray matter, ventral mesencephalon,various hypothalamic nuclei, and lateral parabrachialnucleus.

It may be involved in sleep and arousal mechanisms bygating information passing through the thalamus to thecortex and other brain areas.

There is no evidence at this point for abnormalfunctioning of this dopamine pathway in schizophrenia.


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Disorders associated with

dopaminergic system

Parkinsonism : Decrease Dopamine.

It occurs in substantia nigra Leading to symptoms like

rigidity ,

bradykinesia and

tremors


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Substance Abuse Substance Abuse :

Nucleus Accumbens is a center for reward.

Occurs due to increased release of dopamine causedby the psychotropic substances like morphin

heroin

Cannabis

cocaine

nicotine

REWARD PATHWAY


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REWARD PATHWAY


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Schizophrenia Schizophrenia :

Increase And Decrease Of Dopamine

In Different Region Of Brain.

Mesolimbic pathways

Mesocortical pathways


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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 PsychomotorAgitation/Retardation


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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.


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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


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Reference Kaplan & Sadock's Comprehensive Textbook ofPsychiatry

Stahl's essential psychopharmacology

Internet


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THANK YOU

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