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![NMS
Acute dopamine antagonism (of
hypothalamo spinal tracts) by anti
psychotics may alter sympathetic
nervous system function
Manifestations include increased
muscle metabolism and tone (due to
increased intracellular [Ca2+]), which
elevate creatine phosphokinase](https://image.slidesharecdn.com/dopamine-161117180920/75/Dopamine-36-2048.jpg)
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Dopamine
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- 2. DOPAMINE- INTRODUCTION • Family- Catecholamines(monoamines) • 4-(2-aminoethyl)benzene-1,2-diol • Can act as inhibitory or excitatory • Central and peripheral actions • L-DOPA • precursor of dopamine • cross BBB • L-dihydroxy Phenylalanine • Octopamine - insects
- 3. HISTORY • 1910- firstsynthesised by • George Barger and • James Ewens(London) • 1940s Peter Holtz • Dopa decarboxylase enzyme • Oleh Hornykiewicz(1956)- in parkinsons disease, l-dopa • Arwid Carlsson(1958,2000) dopamine as neurotransmitter
- 4. ARWID CARLSSON- ’father ofdopamine’ OLEH HORNYKIEWICZ
- 5. SYNTHESIS • Site ofsynthesis- neural tissue adrenal medulla • From AA- tyrosine • Rate limiting enzyme Tyrosine Hydroxylase • NA & Adrenaline formed in same pathway • HVA-Final metabolite
- 6. • Phenylalanine • L-tyrosine +OH •L-DOPA -COOH • Dopamine +OH • Norepinephrine +CH3 • Epinephrine
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- 8. SITES • Midbrain • Substantianigra • ventral tegmental area • periaqueductal gray • Hypothalamus • olfactory bulb • Retina • In the periphery-kidney (adr medulla) • Dopaminergic Pathways 1) nigrostriatal, (2) mesocortical (3)mesolimbic, (4) tuberohypophyseal
- 9. DOPAMINERGIC RECEPTORS • MetabotropicG protein coupled receptors • linked to heterotrimeric GTP- binding (G) proteins. • D1, D2a, D2b, D3, D4, and D5 • Dopamine as endogenous ligand • cAMPactivated through adenyl cyclase
- 10. DOPAMINE RECEPTORS • D1-likefamily • D1 and D5 receptors • cAMP by activating the stimulatory G protein, Gs. • D2-like family • D2, D3, and D4 receptors • cAMP-by activating the inhibitory G protein, Gi
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- 14. Areas of greatestconcentration of 5 different type of dopamine receptor D1 D5 D2 D3 D4 Frontal cortex X X X Caudate/putamen X X X Amygdala X Nuc.Accumbens X X X Ventral pallidum X X X Hippocampus X Hypothalamus X Substantia nigra X Brainstem X
- 15. Receptor Subtype D1 D5 D2D3 D4 Gprotein Gs Gs Gi Gi Gi localisation Caudate, putamen, nucleus accumbens olfactory tubercle Hippocam us, hypothala mus Caudate, putamen, nucleus accumbens olfactory tubercle Nucleus accumbens olfactory tubercle, islands of Calleja Frontal cortex, midbrain, amygdala, cardiovasc lar system Likely Physiologic al Role Locomotio n, reward, reinforcem ent, learning and memory, renin secretion Learning and memory Locomotio n, reward, reinforcem ent, learning and memory Locomotio n, possible role in cognition and emotion Mostly unknown - possible role in cognition and emotion, hypertensi n
- 16. FUNCTIONS • Precursor • NEEpinephrine •Neurotransmitter • Neurohormone • prolactin • Pleasure • Reward • emotion • Memory • Attention • Learning • Locomotion • smooth and • controlled muscular movements • Renal- • vasodilation, diuresis, and natriuresis
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- 18. • Mesocortical cognition attention memory • Mesolimbic emotion reward(motivation,pleasure) •Nigrostriatal locomotion • Tuberohypophyseal prolactin
- 20. MESOCORTICAL Located inventral tegmental area of the ventral striatum Send Ascending Projections to prefrontal cortex Involved in working memory predominantly mediated by D1 receptors, attention, goal- directed behavior, reward, and learning
- 21. MESOLIMBIC DOPAMINE PATHWAY • hyperactivein schizophrenia • mediate the positive symptoms of psychosis-Delusions,hallucinations • Dopaminergic projection arising from VTA project to ventral striatum, NA, amygdala, hippocampus and septal area.
- 23. Nigrostriatal pathway dopamine cellbodies → located in pars compacta division of substantia nigra send ascending projections to caudate and putamen modulate motor functions blockade- extra pyramidal symptoms adverse effect of anti psychotic drug
- 24. Tuberohypophyseal dopamine neurons in hypothalamicarcuate and peri ventricular nuclei projections to the pituitary gland inhibitory regulation of prolactin release dopamine antagonist → disinhibition of release → galactorrhoea
- 25. STRIATO - FRONTALCIRCUITS • Intricate connectivity of striatum with the prefrontal cortex and limbic system cognition, regulation of motivation and emotion • Dopamine place a fundamental role • Release of dopamine from the nigrostriatal projections is considered to have a facilitative effect in the direct pathway and inhibitory effect in the indirect pathway • Produce opposing effects on the thalamic targets of basal ganglia outflow to respectively facilitate or suppress cortically initiated activity
- 26. Pathways Dopamine increase disorders Dopamine decrease disorders mesocortica l hyperattentivenes s,racing expansive cognition, overinterpretation of sensory stimuli, impaired ability to self-monitor, grandiosity, euphoria. mania, psychostim ulant abuse. orbito-frontal PFC to caudate, with concomitant overactivity in anterior caudate, from pre- motor PFC to putamen, concomitant dopaminergic overactivity in the putamen and related structures obsessive-compulsive disorder. Tourette's syndrome.
- 27. mesolimbic emotional hyper- reactivity, loss ofcontact with reality including hallucinations and delusions (psychosis). schizophrenia , psychostimula nt abuse, extreme forms of mood disorders. emotional blunting, lack of motivation, and anhedonia. schizophrenia , mood disorders, addictions nigrostriatal dyskinetic movements tardive dyskinesia EPS- rigidity,tremor, ,bradykinesia parkinsonism tuberoinfundi bular Decrease prolactin Increase prolactin galactorrhea DOPAMINE
- 28. DA & SCHIZOPHRENIA Mesolimbic+ve symptoms Mesocortical DLPFC- Cognitive and negative symptoms VLPFC- Cognitive and affective symptoms DOPAMINE HYPOTHESIS
- 29. DOPAMINE HYPOTHESIS • Thedopamine hypothesis for schizophrenia was posed some 40 years ago (Carlsson and Lindqvist 1963), • evidence in living humans supporting this hypothesis has been lacking until recently. • Positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging techniques • amphetamine administration / reserpine that blocks dopamine production.
- 30. DOPAMINE IN MANIA MOOD GRANDIOSITY FLIGHTIOF IDEAS DISTRACTABILITY DECREASED SLEEP GOAL DIRECTED ACTIVITY
- 31. DEPRESSION • Psychomotor retardation– NS system • Emotional expression, learning and reinforcement, hedonic capacity- ML system • Motivation, Concentration, executive and Cognitive tasks- MC system • HP Axis dysfunction- TI system • Monoamine hypothesis-NE,HT,DA Decrease in dopamine
- 32. DA IN ANXIETYDISORDERS • Acute stress DA release • Activates DA release in mPFC • Inhibits DA release in NA • PTSD, Panic – increased plasma DA and HVA concentration
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- 34. EATING DISORDERS • Eating,hunger and reward circuits • VTA-NA-A • Dopamine projections to mammillary body of Hypothalamus->extend to NA • Hunger and reward circuits are interconnected IMPULSE CONTROL DISORDERS • Linked to reward circuitry • BPD • Kleptomania • Pyromania • Sexual addictions paraphilias fetichism pedophilia
- 35. PARKINSONISM • Neuroleptic-induced Blokadeof dopamine D- 2 receptors • All antipsychotic can cause the symptoms • Muscle rigidity,Shuffling gait,Stooped posture,drooling,Tremor affecting lips-Rabbit syndrome • Treated with Anticholinergics Benztropin,Amantadine etc
- 36. NMS Acute dopamine antagonism(of hypothalamo spinal tracts) by anti psychotics may alter sympathetic nervous system function Manifestations include increased muscle metabolism and tone (due to increased intracellular [Ca2+]), which elevate creatine phosphokinase
- 37. TARDIVE DYSKINESIA Delayed effectof antipsychotic Chewing& sucking ,Grimacing, Chorioathetoid movements • Supersensitivity to dopamine –Prolonged dopaminergic blockade Limiting long term antipsychotic treatment Using atypical agents
- 38. DA AND ACH EPS DR ANTAGONISTS Dopamineand acetylcholine
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- 40. D2 receptorblockade is associated with efficacy of antipsychotic drugs Longterm administration result in up regulation in the number of receptor → tardive dyskinesia. Serotonin Dopamine antagonist block 5HT.2 and lesser extend D2 receptors → decreased risk for parkinsonism → effective for +ve and –ve symptoms of schizophrenia. DOPAMINE AND DRUGS
- 41. Amphetamine →release of dopamine Cocaine → Block uptake of dopamine Cocaine & methamphetamine → addicting substance → Dopaminergic system is involved in reward or pleasure seeking system Dopamine transporter is required or pharmacological effect of cocaine DOPAMINE AND DRUGS
- 42. Nicotine →Psychoactive ingredient in cigarette → Stimulate release of dopamine & glutamate Smokers - decreased risk of Parkinson disease, Alzheimers disease, ulcerativecolitis Dopamine transporter can be blocked by Buproprion. DOPAMINE AND DRUGS
- 43. Used totreat adverse effect of antipsychotic drugs Parkinsonism, EPS, akinesia, NMS, Focal perioral tremors, hyperprolactinemia galactorrhoea Bromocriptine, L Dopa & Carbi Dopa, Rapinirole, pramipexole, pergolide, apomorphine., DOPAMINE RECEPTOR AGONIST & PRECURSORS
- 44. Typical antipsychotics Phenothiazines → chlropromazine, promazine, Triflupromazine Thioxanthines → chlorprothixene Butyrophenones → Haloperidol. DOPAMINE RECEPTOR ANTAGONIST
- 45. Atypical antipsychotics 2nd generation anti psychotics Rispiridone ; olanzapine ; quietiapine ; clozapine ; ziprasidone Characteristics → Low D2 receptor blockade → Decreased EP side effect → Increased Efficacy in schizophrenia & a / c Mania SEROTONINE – DOPAMINE ANTAGONIST
- 46. REFERENCES • COMPREHENSIVE TEXTBOOKOF PSYCHIATRY • BRAIN AND BEHAVIOR • STAHL’S ESSENTIAL PSYCHOPHARMACOLOGY