Dopamine

Arvid CarlssonGöteborg

Nobel price 2000

Dopamine (DA)

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

Specific toxins

6-hydroxy – dopamine (6-OH-DA)

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

CORTEX

STRIATUMGPe GPi

SNrTHAL

SNc STN

GLU

GLU

GLU

DA

GABA GABA

GABAGABA

GABA

GABAGABA

D1

D2

GLU

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

Reward

Res

pons

e No CS

Reward

Res

pons

e CS

No reward

Res

pons

e CS

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)

Dopamin Aktivität

Vermindert normal erhöht

Akinesie willentliche Hyperkinesie Bewegung

Verlangsamt „switching“ gesteigert

Verlangsamt Gewohnheitslernen gesteigert

Parkinson-K. Schizophrenie