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4.4. Dopamine and the dopaminergic receptors

4.4. Dopamine and the dopaminergic receptors - Catecholamines [dopamine, 3,4-dihydroxyphenyl- b -ethylamine] - DA receptor [80% in corpus striatum; 20% in brain cortex] - DA for psychosis and movement disorders (PD) / vascular receptor interaction. 4.4.1. Dopamine metabolism and receptors

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4.4. Dopamine and the dopaminergic receptors

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  1. 4.4. Dopamine and the dopaminergic receptors - Catecholamines [dopamine, 3,4-dihydroxyphenyl-b-ethylamine] - DA receptor [80% in corpus striatum; 20% in brain cortex] - DA for psychosis and movement disorders (PD) / vascular receptor interaction

  2. 4.4.1. Dopamine metabolism and receptors - Catecholamine biochemistry - DA in synaptic vesicles - DA deactivation mechanism [reuptake / MAO / COMT]

  3. 4.4.1. Dopamine metabolism and receptors - Receptors D1-like receptor (+ AC): D1 & D5 / D2-like receptor (- AC): D2, D3, D4 - D2 receptor & antipsychotic drugs - antipsychotic molecules (haloperidol, chlorpromazine, clozapine) relative affinities of D2, D3, D4 - long-term administration of antipsychotic agents D2 receptor in basal ganglia region / PD-like movement disorder Motor dysfunction and D2-receptor density 4.4.2. Presynaptic dopaminergic drug effects 1) dopamine synthesis inhibitors 2) dopamine metabolism inhibitors 3) dopamine storage inhibitors 4) dopamine reuptake inhibitors 5) presynaptic dopaminergic agonists 4.4.2.1. Dopamine synthesis inhibitors - a-methyltyrosine: tyrosine hydroxylase inhibitor - carbidopa: dopa decarboxylase inhibitor DOPA protection from peripheral decarboxylase / no-BBB crossing

  4. - carbidopa: dopa decarboxylase inhibitor coadministration between dopa and carbidopa [benserazide] - DL-a-fluoromethyldopa: arylamide acid decarboxylase inhibitor via covalent binding complete inhibition of catecholamine and serotonin synthesis cf) 6-hydroxydopamine: neuronal destruction reserpine: depletion of chromaffin tissue 4.4.2.2. Dopamine metabolism inhibitors - DA breakdown enzymes: monoamine oxidase & catecholamine O-methyl transferase

  5. 4.4.2.3. Dopamine storage inhibitors - reserpine: storage and release of DA - g-hydroxybutyrate and butyrolactone: inhibiting DA release / crossing BBB - amphetamine: vesicle depletion - amantadine: DA release / antiviral drug [PD, multiple sclerosis]

  6. 4.4.2.4. Dopamine reuptake inhibitors - benztropine and amphetamines: DA reuptake inhibitor - tandamine, bupropion, nomifensine: DA reuptake inhibitor [antidepressant] 4.4.3. Postsynaptic dopaminergic drug effects 4.4.3.1. Dopamine agonists - extended b-phenethylamine structure with trans configuration (1) (-)-apomorphine emetic effect, hydroxyl group, treatment of erectile dysfunction modifications (N-alkylation, b-hydroxylation of DA, a-methyl substitution central DA activity 감소, adenylate cyclase interaction 증가

  7. 4.4.3.1. Dopamine agonists (2) 6,7-dihydroxy-2-aminotetraline (ADTN) (3) nomifensine: antidepressant catechol analog: NE & DA uptake (4) ergot alkaloids indole peptide alkaloids ergocryptine: a-adrenergic antagonist dihydro-derivative: D2 agonist / vasodilator / geriatric performance enhancer hypotensive effect smooth muscle contraction (uterus) cf) lysergic acid [tetracyclic indole acid] amides: hallucinogen (5) bromocriptine parkinsonism prolactin secretion inhibition (lactation control) GH inhibition (acromegaly treatment)

  8. Dopamine in Parkinson’s disease 1. Synthesis 2. Storage 3. Release 4. Binding 5. Reuptake 6. Degradation

  9. 4.4.3.2. Dopamine antagonists (Neuroleptics) - antidopaminergics: therapy for psychosis - psychosis (1) Schizophrenia thought disorder misinterpretation of reality delustions and hallucinations “splitting of the mind” * fragmentation between thought content and emotional response (2) Paranoid delusions (generally persecutory but sometimes grandiose) (3) Affected psychosis mood disorder & extreme depression * complicated assortment of psychiatric illness - dopamine antagonists: antipsychotic drugs (neuroleptics) / symptomatic management - chlorpromazine (1952 by Delay and Daniker) antihistamine properties major sedative action

  10. - Tricyclic thymoleptics derived from chlorpromazine as neuroleptics (1) phenothiazine a calming effect on psychotic patients w/o excessive sedation antiemetic effect ring nitrogen & side chain nitrogen shorter chain (promethozine): antihistamine with strong sedative action ring substituent at position 2: electron attracting (2) thioxanthenes w/o the ring nitrogen of phenothiazine cis-isomer DA-sensitive AC of the striatum inhibition (3) butyrophenones: antipsychotics / antiemetics / potentiate anesthetics pimozide derived from benperidol (4) atypical neuroleptics clozapine / risperidone / olanzapine / sertindole 5-HT2 serotonin receptor & D2 R clozapine: D4R, H1 histamine R, muscarinic Ach R bone marrow failure (agranulocytosis) as side effect

  11. - DA receptor and psychiatric illness antipsychotic neuroleptics: D2R blockage haloperidol binding inhibition vs. apomorphine inhibition - Common side effects of many antipsychotics (1) extrapyramidal symptoms rigidity & tremor / continuous restless walking / facial grimacing / tardive dyskinesia (2) complex cardiovascular side effects and antimuscarinic activity (3) sedation & hypotension [a-adrenergic activity] - Other than antidopaminergic neuroleptics: origin of schizophrenia neurotensin: antipsychotic effect (modulation of DA release) cholecystokinin: DA release inhibition cf) schizophrenia: CCK & somatostain glutamate, adenosine, and serotonin - No molecular insights about the nature, etiology, or biochemistry of psychotic disorders

  12. 4.4.4. The clinical-molecular interface: PD as dopaminergic disorder - deterioration of the dopaminergic neuronal pathways: Parkinson’s disease - movement disorder [resting tremor, akinesia, rigidity, stooped posture, shuffling gait, speech and swallowing difficulties] - incurable and slowly progressing disease - PD mechanism reserpine ---- akinesia (by depletion of central catecholamine stores) PD patient: extremely low DA level designer drug contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) MPP+: dopaminergic neurotoxin - PD and DA deficiency in the brain: DA replacement L-dopa: prodrug of DA akinesia and rigidity side effects: nausea / vomiting / uncontrolled movement (limb dyskinesia) carbidopa or benserazide: peripheral DOPA decarboxylase inhibitors preventing peripheral DA formation emetic at the vomiting center in the brainstem prolonged administration L-dopa: involuntary movements 4-5 years: resistant to L-dopa

  13. - Ergot derivatives: DA receptor agonists bromocriptine, lisuride, cabergoline, pergolide - Non-ergot compounds ropinirole, pramipexole

  14. - amantadine: mobilizing DA stores NMDA ligand-gated ion channels (blockade) --- Ach release ---- DA/Ach ratio in PD cf) anticholinergics: tremor suppression in PD dopaminergics: better for bradykinesia (slow movement) - PD therapy: enzyme inhibitor MAO inhibitor: selegiline (dopamine breakdown inhibition) COMT inhibitor: entacapone & tolcapone --- L-dopa and dopamine level - antimuscarinic anticholinergic agents: antiparkinsonism drugs removal of inhibiting dopaminergic effects --- exaggerating the excitatory cholinergic functions antagonists at muscarinic cholinoceptos benztropine or biperiden: inhibition of striatal cholinergic overactivity improving tremor & rigidity (not akinesia)

  15. - side effects: DA and Ach manipulation anticholinergics: tremor of DA / worsen symptoms of dementia inverse relationship between PD and psychosis PD: DA deficiency with dopaminergics [confusion, psychotic delusions] psychosis: DA excess with antidopaminerics [Parkinson’s features]

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