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Dopamine

Dopamine. Arvid Carlsson Göteborg. Nobel price 2000. Dopamine (DA). Presynapse Tyrosine Tyrosine hydroxylase L-DOPA L-DOPA decarboxylase Vesicular- Membrane- Dopamine

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Dopamine

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  1. Dopamine Arvid Carlsson Göteborg

  2. Nobel price 2000

  3. Dopamine (DA)

  4. Presynapse Tyrosine Tyrosine hydroxylase L-DOPA L-DOPA decarboxylase Vesicular- Membrane- Dopamine Transporter------------------------------------------------------------ reuptake Synapt. cleftMAO, COMT ---------------------------------------------------------------------------- Postsynapse excitatory R: metabotropic D1 and D5 inhibitory R: metabotropic D2, D3, D4

  5. Pharmacology of the DAergic synapse Presynpase -inhibition of tyrosine-hydroxylase by - alpha-methyl-para-tyrosine (AMPT) - inhibition of DOPA decarboxylase - destruction of storage vesicles by reserpine or tetrabenazine - blockade of vesicular transporter and carrier mediated DA release by amphetamines. Transporter - reuptake-inhibition by: Cocaine, Amphetamine, Nomifensine Synapt. cleft - MAO-inhibitors, COMT-inhibitors

  6. Dopamin Apomorphin Dopamine Receptors D1 D5 D2 D3 D4 Excitatory excit. Inhibitory inibit. Direct agonists SKF 38393 Dihydrexidine BP897 (partial) Pramipexol Pergolide Bromocriptin Lisuride Quinpirol Direct antagonists Haloperidol Chlorpromazin Sulpiride Raclopride SCH 23390 Nafadotride

  7. Indirect agonists Praesynaptic: L-Dopa Amphetamin Cocain Reuptake -Inhibitor: Amphetamin Cocain Nomifensin MAO-Inhibitors: Deprenyl Nialamid Tranylcypromin COMT-Inhibitors Indirect antagonists ΑMPT (alpha-methyl- Para-tyrosin) Reserpin Tetrabenazin Toxine: 6 OH-Dopamine MPTP Rotenone

  8. Specific toxins 6-hydroxy – dopamine (6-OH-DA) MPTP Rotenone

  9. Pros cons 6-OH-dopamine Selective for Does not penetrate monoaminergic neurons the BBB, taken up by MA-transporters local infusion required MPTP Crosses BBB works only in primates some mice strains, not in rats. Rotenone Crosses BBB unselective in high works in rats doses Lewy body formation Chronic model

  10. Neuroanatomy Midbrain Striatum = Substantia nigra nigro- Nucleus Caudatus striatal projectionPutamen Ventral tegmental Nucleus accumbens area (VTA) meso-limbic prefront. Cortex projection

  11. CORTEX GLU GLU GLU GABA GABA THAL STRIATUM ACH SNr D1(+) GPi GPe D2(-) GABA GABA GABA DA GABA GABA GLU SNc STN GLU DA

  12. CORTEX GLU GLU GLU GABA GABA THAL STRIATUM SNr D1(+) GPi GPe D2(-) GABA GABA GABA DA GABA GABA GLU GLU SNc STN DA Neuropharmacology Uni-Tuebingen

  13. CORTEX GLU GLU GLU GABA GABA THAL STRIATUM SNr D1(+) GPi D2(-) GPe D1(+) GABA GABA GABA DA GABA GABA GLU GLU SNc STN DA

  14. CORTEX GLU GLU GLU GABA GABA THAL STRIATUM D1(+) SNr GPi GPe D2(-) GABA GABA GABA DA GABA GABA GLU GLU SNc STN DA

  15. CORTEX GLU GLU GLU GABA GABA THAL STRIATUM D1 SNr GPi GPe D2 GABA GABA GABA DA GABA GABA GLU SNc STN

  16. Physiology of dopamine Nigro srtiatal projection: Spontaneitiy, switching Intended actions Motor learning, habit learning Egocentric representation of the body in space Mesolimbic projection Reward prediction Approach, appetence Part of the brain reward system

  17. mental: all brain capacities cognitive: higher brain functions learning conscious declarative HIPPOCAMPUS TEMPORAL LOBE unconscious non-declarative BASAL GANGLIA mutual inhibitory knowledges skills, motor and cognitive adaptive behaviour rule like behaviour = habits extinguishable not-extinguishable Time course: conscious incrementally acquired habit control associations

  18. No CS Reward Response CS Reward Response CS No reward Response

  19. Pathophysilogy of dopamine (DA) Reduced DA activity in the nigro striatal projection Bradykinesia, swiching deficit (motor and cognitive) Akinesia, Rigor, Tremor (Symptoms of Parkinson‘s disease) Deficits in implicit learning (Symptoms...) Reduced DA activity in the mesolimbic projection Reduced appetence, drive Reduced activity of the brain reward system

  20. Enhanced DA activity in the nigrostriatal projection Hyperactivity, hyperkinesia Stereotypy Enhanced activity in the mesolimbic projection Enhanced appetence, drive Addiction Schizophrenia (??? according to DA-hypothesis)

  21. Dopamin Aktivität Vermindert normal erhöht Akinesie willentliche Hyperkinesie Bewegung Verlangsamt „switching“ gesteigert Verlangsamt Gewohnheitslernen gesteigert Parkinson-K. Schizophrenie

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