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Dopamine Arvid Carlsson Göteborg. Nobel price 2000.

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Presentation on theme: "Dopamine Arvid Carlsson Göteborg. Nobel price 2000."— Presentation transcript:

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. cleft MAO, COMT Postsynapse excitatory R: metabotropic D1 and D5 inhibitory R: metabotropic D2, D3, D4

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6 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

7 Dopamine Receptors D1D5D2D3D4 Excitatory excit. Inhibitory inibit. Direct agonists Dopamin Apomorphin SKF Dihydrexidine Pramipexol Pergolide Bromocriptin Lisuride Quinpirol BP897 (partial) Direct antagonists SCH Haloperidol Chlorpromazin Sulpiride Raclopride Nafadotride

8 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

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

10 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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16 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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18 CORTEX STRIATUM GPe GPi SNr ACH THAL SNcSTN GLU DA GABA D1(+) D2(-) GLU

19 CORTEX STRIATUM GPe GPi SNr THAL SNcSTN GLU DADA GABA D1(+) D2(-) GL U DA GLU N europharmacology Uni-Tuebingen

20 CORTEX STRIATUM GPe GPi SNr THAL SNcSTN GLU DA GABA D1(+) D2(-) D1(+) GLU

21 CORTEX STRIATUM GPe GPi SNr THAL SNcSTN GLU DADA GABA D1(+) D2(-) GLU DA

22 CORTEX STRIATUM GPe GPi SNr THAL SNcSTN GLU DADA GABA D1 D2 GLU

23 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

24 mental: all brain capacities cognitive: higher brain functions learning conscious declarative HIPPOCAMPUS TEMPORAL LOBE unconscious non-declarative BASAL GANGLIA mutual inhibitory knowledges extinguishablenot-extinguishable skills, motor and cognitive adaptive behaviourrule like behaviour = habits Time course: conscious incrementally acquired habit control associations

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26 Reward Response No CS Reward Response CS No reward Response CS

27 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

28 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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31 Dopamin Aktivität Vermindert normal erhöht Akinesie willentliche Hyperkinesie Bewegung Verlangsamt „switching“ gesteigert Verlangsamt Gewohnheitslernen gesteigert Parkinson-K. Schizophrenie


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