DOPAMINE

Dopamine is a crucial neurotransmitter and neuromodulator in the brain, playing significant roles in various physiological and psychological functions. It is synthesized from the amino acid tyrosine through a two-step process involving its precursor, L-DOPA. Dopamine constitutes about 80% of the catecholamine content in the brain and is involved in the regulation of movement, mood, reward, and several other bodily functions
Functions of Dopamine
1. Neurotransmitter Role:
Dopamine acts as a chemical messenger between neurons, facilitating communication within the nervous system. It is particularly important in areas associated with reward and pleasure, such as the ventral tegmental area and nucleus accumbens25.
2. Reward System:
Often referred to as the "feel-good" neurotransmitter, dopamine is released during pleasurable activities (e.g., eating, sex) and reinforces behaviors by creating a sense of reward and motivation42. This mechanism is crucial for learning and habit formation.
3. Motor Control:
Dopamine plays a vital role in coordinating movemen

1. DOPAMINE DR HARI RAM SEDAI 1 ST YEAR RESIDENT PSYCHIATRY/NMCTH

2. Content

3. History

4. Introduction Chemically derived from an amino acid Belongs to a small family of related compounds known as catecholamine Contains a catechol group (benzene ring with two adjacent hydroxyl groups) and an amine group

5. Dopaminergic sites Brain Midbrain Substantia nigra Ventral tegmental area Periaqueductal gray Hypothalamus Outside Brain Olfactory bulb Retina Kidney (Adrenal medulla)

6. Dopamine Synthesis Synthesized from Tyrosine Precursor: L-dopa Rate limiting enzyme : Tyrosine hydroxylase Final step: Decarboxylation from L-dopa Co-factor involved: Pyridoxal phosphate

7. Tyrosine is derived from dietary protein & Phenylaline metabolism E nters brain by Large neutral amino acid (LNAA) metabolism In cytosol: Tyrosine converted to L-dopa by tyrosine hydroxylase Next step: Decrboxylation of L-dopa by aromatic amino acid decarboxylase (AADC) AADC decarboxylates L-dopa so avidly that the level of this amino acid in the brain is very low under normal conditions

8. Transportation VMAT2: Storage and release DAT: Reuptake Presynaptic D2 Auto receptor: R egulates release of DA

9. Vesicular Transport Vesicles in presynaptic terminal is specialized for the uptake and storage of catecholamines by enzyme Monoamine oxidase (MAO) found in mitochondria Vesicular monoamine transporter ( VMAT)- accumulation and concentration of catecholamine transmitters inside the vesicles 2 Forms: VMAT-1 - expressed in extraneuronal tisuue - chromaffin cells VMAT-2 - neuronal cells of cns , pns , enteric nervous system

10. Degradation Centrally: MOA A & MOA B (Mitochondria of presynaptic neuron) MOA-A - located in dopaminergic and non adrenergic neurons MOA-B : Located in serotonergic neurons & glia Peripherally: COMT (extracellular) End product: Homovanillic acid

11. Monoamine Oxidase (MAO) Located on outer membrane of mitochondria MAO-A & MAO-B (Major form) Dopamine and norepinephrine are effective substrates for both forms S erotonin is a preferential substrate for MAO-A MAO-B inhibitor that is used in the treatment of Parkinson disease, usually in combination with L-dopa to prolong or enhance the effect of dopamine formed from L-dopa

12. Catechol-O-Methyl Transferase (COMT) Membrane bound form has higher affinity for catecholamines COMT plays a more significant role in dopamine metabolism in the prefrontal cortex COMT inhibitors- Tolcapone and Entacapone , are used as adjuncts to L-dopa in the treatment of Parkinson disease to slow L-dopa metabolism and thereby prolong its effects

13. Dopamine Receptors D1 like D1 & D5 N igrostriatal , mesolimbic, and mesocortical system D2 like D2, D3, D4 Striatum and nucleus accumbens

14. D1 like Dopamine receptors A ctivate the Gs family of G proteins I ncrease adenylate cyclase activity F ound postsynaptically on dopamine-receptive cells D2-like Dopamine receptors C ouple to the Gi family I nhibit adenylate cyclase activity E xpressed both postsynaptically on dopamine-receptive cells & presynaptically on dopaminergic neurons

15. AADC: A romatic amino acid decarboxylase AC: Adenylate cyclase COMT: C atechol-O- methyltransferase DOPAC: Dihydroxyphenylacetic acid HVA: H omovanillic acid MAO: M onoamine oxidase VMAT: Vesicular monoamine transporter. Schematic model of a dopaminergic synapse with sites of drug action

16. Dopaminergic Pathways

17. Mesolimbic Pathway Carries dopamine from the M idbrain V entral T egmental A rea to the N ucleus A ccumbens via amygdala and hippocampus Motivations, pleasure, reward Positive symptoms (hallucinations, delusions) of schizophrenia Positive symptoms (Impulsive, agitation, aggressive & hostile) of psychosis

18. Mesocortical Pathway Projects from Ventral Tegmental A rea to Prefrontal Cortex Regulates motivation, concentration and initiation of goal-directed and complex executive cognitive tasks Believed to be involved in the negative , cognitive and affective symptoms of schizophrenia

19. Nigrostriatal Pathway Projects from S ubstantia N igra (Pars compacta ) to Striatum (Caudate & putamen) 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 .

20. Tubulofundibular Pathway Projects from A rcuate N ucleus and the P eriventricular area of H ypothalamus to I nfundibulum and A nterior pituitary It regulates prolactin secretion into circulation by inhibiting prolactin secretion

21. Reward Pathway The dopaminergic pathway mostly involved in reward is M esolimbic S ystem F ormed by projections of midbrain dopamine neurons of the ventral tegmental area (VTA) to the striatum, prefrontal cortex, amygdala, hippocampus When rewarding stimuli are experienced, the dopaminergic mesolimbic system is activated which causes the release of dopamine to the targeted nuclei

22. The ventral striatum, including the nucleus accumbens ( NAcc ), is a major substrate involved in reward pathway The dorsal striatum is critically involved in action selection and initiation components of decision making Mediates feedback properties such as valiance and magnitude in addition to controlling habitual behaviour

23. Parkinson disease Degeneration of dopaminergic neurons in the substantia nigra Dysfunction in dorsal striatal dopamine transmission Hypokinesia , rigidity, and tremor originate from a loss of striatal dopaminergic innervation

24. Schizophrenia Excessive dopamine activity in striatal and limbic regions P sychosis symptoms of schizophrenia were associated with increased dorsal/associative striatum dopamine release Negative symptoms and cognitive impairments were associated with reductions in cortical and ventral/limbic striatal dopamine release

25. ADHD Dysfunction of dopaminergic neurotransmission in limbic and cortical regions Less than optimal stimulation of Postsynaptic D1 receptors by Dopamine in Prefrontal cortex D eficiency in dopamine levels, which affects their ability to experience reward and motivation This deficiency can lead to difficulties in focusing, completing tasks, and regulating behaviour

26. References Kaplan & Sadock’s Comprehensive Textbook Of Psychiatry, 11 th edition Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications 4th Edition Textbook of Medical Physiology, Guyton and Hall, 12th edition