DopaminePRESENTATOR: DR PRASHANT

MISHRA

MODERATOR : PROF. V.SHARBANDHRAJ

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.

Types of neurotransmitters• Major neurotransmittersAmino acids: glutamate, aspartate, D-serine, γ-aminobutyric

acid (GABA), glycineMonoamines and other biogenic amines: dopamine (DA), norepinephrine,

epinephrine ,histamine, serotonin (5-HT)Others: acetylcholine (ACh), adenosine, anandamide, nitric

oxide, etc.

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.

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.

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)

StorageDopamine 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.

receptors Adenyl cyclase = produce cyclic AMP

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.

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).

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.

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 hallucinations (B).

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

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

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."

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."

Thalamic dopamine pathwayIt 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.

Disorders associated with dopaminergic system…

Parkinsonism : Decrease Dopamine.It occurs in substantia nigraLeading to symptoms like

rigidity ,bradykinesia and tremors

Substance AbuseSubstance 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

REWARD PATHWAY

SchizophreniaSchizophrenia :

Increase And Decrease Of Dopamine

In Different Region Of Brain.

Mesolimbic pathways

Mesocortical pathways

Depression : Decrease Of Dopamine in following areasVMPFC- Depressed moodPFC, Hypothalamus, Nucleus Accumbens -

Apathy Nucleus Accumbens Striatum Hypothalamus-

FatigueDLPFC- Executive Dysfunction Nucleus Accumbens ,PFC – Psychomotor

Agitation/Retardation

ADHD : Decrease In Dopamine Level in anterior

frontal cortexAn area associated with cognitive function

such as attention concentration.

Impulse Control Disorder : Decrease In Dopamine Level.

DRUGS AFFECTING DOPAMINERGIC SYSTEM…

Dopamine Agonist:LevodopaCarbidopa Ropinirole

Antidepressent:Bupuropion

Antipsychotics:Typical antipsychotic like halopoperidol, pimozide, Atypical antipsychotics like olanzapine, quetiapine,

resperidone etcStimulants:

MethylphenidateModafinilArmodafinil

Reference Kaplan & Sadock's Comprehensive Textbo

ok of PsychiatryStahl's essential psychopharmacologyInternet

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