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Dopamine Arvid Carlsson Göteborg
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Nobel price 2000
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Dopamine (DA)
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Postsynapse excitatory R: metabotropic D1 and D5
Presynapse Tyrosine Tyrosine hydroxylase L-DOPA L-DOPA decarboxylase Vesicular- Membrane Dopamine Transporter reuptake Synapt. cleft MAO, COMT Postsynapse excitatory R: metabotropic D1 and D5 inhibitory R: metabotropic D2, D3, D4 Accumulation within the vesicle versus cytoplasm: : 1 (Kostrzewa et al. 2005, Amino Acids 28)
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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
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Dopamine Receptors D1 D5 D2 D3 D4 Excitatory excit Inhibitory inibit. Direct agonists Dopamin Apomorphin SKF 38393 Dihydrexidine Pramipexol Pergolide Bromocriptin Lisuride Quinpirol BP897 (partial) Direct antagonists Haloperidol Chlorpromazin Sulpiride Raclopride SCH 23390 Nafadotride
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Indirect agonists Praesynaptic: L-Dopa Amphetamin Cocain Reuptake -Inhibitor: Amphetamin Nomifensin MAO-Inhibitors: Deprenyl Nialamid Tranylcypromin COMT-Inhibitors Indirect antagonists ΑMPT (alpha-methyl- Para-tyrosin) Reserpin Tetrabenazin Toxine: 6 OH-Dopamine MPTP Rotenone
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Specific toxins 6-hydroxy – dopamine (6-OH-DA) MPTP Rotenone
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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
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Neuroanatomy Midbrain Striatum =
Substantia nigra nigro Nucleus Caudatus striatal projection Putamen Ventral tegmental Nucleus accumbens area (VTA) meso-limbic prefront. Cortex projection
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CORTEX THAL SNr GPi GPe SNc STN STRIATUM ACH D1(+) D2(-) GLU GLU GLU
GABA GABA THAL STRIATUM ACH D1(+) SNr GPi GPe D2(-) GABA GABA GABA DA GABA GABA GLU SNc STN GLU DA
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CORTEX GPe GPi SNr THAL SNc STN Neuropharmacology Uni-Tuebingen
STRIATUM GPe GPi SNr THAL SNc STN GLU DA GABA D1(+) D2(-) Neuropharmacology Uni-Tuebingen
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CORTEX THAL SNr GPi GPe SNc STN STRIATUM D1(+) D2(-) D1(+) GLU GLU GLU
GABA GABA THAL STRIATUM SNr D1(+) GPi D2(-) GPe D1(+) GABA GABA GABA DA GABA GABA GLU GLU SNc STN DA
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CORTEX THAL SNr GPi GPe SNc STN STRIATUM D1(+) D2(-) GLU GLU GLU GABA
DA GABA GABA GLU GLU SNc STN DA
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CORTEX THAL SNr GPi GPe SNc STN STRIATUM D1 D2 GLU GLU GLU GABA GABA
DA GABA GABA GLU SNc STN
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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
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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
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Reward Response No CS Reward Response CS CS No reward Response
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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
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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)
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Dopamin Aktivität Vermindert normal erhöht Akinesie willentliche Hyperkinesie Bewegung Verlangsamt „switching“ gesteigert Verlangsamt Gewohnheitslernen gesteigert Parkinson-K Schizophrenie
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