PRESENTATOR: DR PRASHANT MISHRAMODERATOR : 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 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.
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 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 packagedinto synaptic vesicles via the vesicular monoamine transporter (VMAT2) andstored 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)
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.
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 primarybinding site for virtually all antipsychotic agents as well as for dopamine agonists used totreat Parkinsons disease.
Presynaptic dopamine-2 autoreceptors are "gatekeepers" for dopamine. That is,when these gatekeeping receptors are not bound by dopamine (no dopamine inthe gatekeepers hand), they open a molecular gate, allowing dopamine release(A). However, when dopamine binds to the gatekeeping receptors (now thegatekeeper has dopamine in his hand), they close the molecular gate andprevent 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 tegmentalarea in the brainstem to the nucleus accumbens in the ventral striatum (A), isinvolved in regulation of emotional behaviors and is believed to be thepredominant pathway regulating positive symptoms of psychosis. Specifically,hyperactivity of this pathway is believed to account for delusions and
ventral tegmental area to the prefrontal cortex .(DLPFC) are believed to beinvolved in the negative and cognitive symptoms of schizophrenia
Mesocortical dopamine projections specifically to the ventromedial prefrontalcortex (VMPFC) are believed to mediate negative and affective symptomsassociated with schizophrenia.
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 ticsand dyskinesias. In untreatedschizophrenia, activation of thispathway is believed to be"normal."
from hypothalamus toanterior pituitaryregulates prolactinsecretion into thecirculation. Dopamineinhibits prolactinsecretion. In untreatedschizophrenia,activation of thispathway is believed tobe "normal."
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.
Disorders associated withdopaminergic system… Parkinsonism : Decrease Dopamine. It occurs in substantia nigra Leading to symptoms like rigidity , bradykinesia and tremors
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
Schizophrenia Schizophrenia : Increase And Decrease Of Dopamine In Different Region Of Brain. Mesolimbic pathways Mesocortical pathways
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
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.