Dopamine Arvid Carlsson Göteborg

Nobel price 2000

Dopamine (DA)

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: 135 000 : 1 (Kostrzewa et al. 2005, Amino Acids 28)

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

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

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

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

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

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

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

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

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

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

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

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

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

Reward Response No CS Reward Response CS CS No reward Response

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

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)

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