dopamine arvid carlsson göteborg. nobel price 2000
TRANSCRIPT
Presynapse Tyrosine Tyrosine hydroxylase
L-DOPA L-DOPA decarboxylase
Vesicular-Membrane- DopamineTransporter------------------------------------------------------------ reuptake Synapt. cleft MAO, COMT----------------------------------------------------------------------------
Postsynapse excitatory R: metabotropic D1 and D5
inhibitory R: metabotropic D2, D3, D4
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, NomifensineSynapt. cleft - MAO-inhibitors, COMT-inhibitors
Dopamine Receptors
D1 D5 D2 D3 D4Excitatory excit. Inhibitory inibit.
Direct agonists
Dopamin
Apomorphin
SKF 38393Dihydrexidine
PramipexolPergolide Bromocriptin Lisuride Quinpirol
BP897(partial)
Direct antagonists
SCH 23390HaloperidolChlorpromazin SulpirideRaclopride
Nafadotride
Indirect agonists Praesynaptic: L-Dopa
AmphetaminCocain
Reuptake-Inhibitor: Amphetamin
CocainNomifensin
MAO-Inhibitors: Deprenyl
NialamidTranylcypromin
COMT-Inhibitors
Indirect antagonists ΑMPT (alpha-methyl-Para-tyrosin) Reserpin Tetrabenazin Toxine: 6 OH-Dopamine
MPTP Rotenone
Pros cons 6-OH-dopamineSelective for Does not penetrate monoaminergic neurons the BBB, taken up by MA-transporters local infusion required
MPTPCrosses BBB works only in primates some mice strains, not in rats. RotenoneCrosses BBB unselective in highworks in rats dosesLewy body formationChronic model
Neuroanatomy
Midbrain Striatum =Substantia nigra nigro- Nucleus Caudatus striatal projection Putamen
Ventral tegmental Nucleus accumbensarea (VTA) meso-limbic prefront. Cortex projection
CORTEX
STRIATUMGPe GPi
SNrACH
THAL
SNc STN
GLU
GLU
GLUGLU
DA
DA
GABA GABA
GABA GABA GABA
GABAGABAD1(+)
D2(-)
GLU
CORTEX
STRIATUMGPe GPi
SNrTHAL
SNc STN
GLU
GLU
GLU
DA
GABAGABA
GABAGABA GABA
GABAGABA
D1(+)
D2(-)
GLUDA
GLU
Neuropharmacology Uni-Tuebingen
CORTEX
STRIATUMGPe GPi
SNrTHAL
SNc STN
GLU
GLU
GLUGLU
DA
DA
GABA GABA
GABA GABA GABA
GABAGABA
D1(+)
D2(-)D1(+)
GLU
CORTEX
STRIATUMGPe GPi
SNrTHAL
SNc STN
GLU
GLU
GLUGLU
DA
GABA GABA
GABA
GABA
GABA
GABAGABA
D1(+)
D2(-)
GLU
DA
Physiology of dopamine
Nigro srtiatal projection: Spontaneitiy, switchingIntended actionsMotor learning, habit learningEgocentric representation of the body in space
Mesolimbic projectionReward predictionApproach, appetencePart of the brain reward system
mental: all brain capacitiescognitive: higher brain
functionslearning
consciousdeclarativeHIPPOCAMPUSTEMPORAL LOBE
unconsciousnon-declarativeBASAL GANGLIA
mutual inhibitory
knowledges
extinguishable not-extinguishable
skills, motor and cognitive
adaptive behaviour rule like behaviour = habits
Time course:
conscious incrementally acquired habit
control associations
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, driveReduced activity of the brain reward system
Enhanced DA activity in the nigrostriatal projection
Hyperactivity, hyperkinesiaStereotypy
Enhanced activity in the mesolimbic projection
Enhanced appetence, driveAddictionSchizophrenia (??? according to DA-hypothesis)