Modulatory effects of L-DOPA on D2 dopamine receptors in rat striatum, measured using in vivo microdialysis and PET.
Putative modulatory effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on D2 dopamine receptor function in the striatum of anaesthetised rats were investigated using both in vivo microdialysis and positron emission tomography (PET) with carbon-11 labelled raclopride as a selective D2 receptor ligand. A single dose of L-DOPA (20 or 100mg/kg i.p.) resulted in an increase in [11C]raclopride binding potential which was also observed in the presence of the central aromatic decarboxylase inhibitor NSD 1015, confirming that the effect was independent of dopamine. This L-DOPA evoked D2 receptor sensitisation was abolished by a prior, long-term administration of L-DOPA in drinking water (5 weeks, 170mg/kg/day). In the course of acute L-DOPA treatment (20mg/kg), extracellular GABA levels were reduced by approximately 20% in the globus pallidus. It is likely that L-DOPA sensitising effect on striatal D2 receptors, as confirmed by PET, may implicate striato-pallidal neurones, hence a reduced GABA-ergic output in the projection area. Since the L-DOPA evoked striatal D2 receptor supersensitivity habituates during long-term treatment, the effects reported here may contribute to the fluctuations observed during chronic L-DOPA therapy in Parkinson's disease.
PET Methodology Group, MRC Cyclotron Unit, Hammersmith Hospital, London, United Kingdom.
J
J
Opacka-Juffry
S
S
Ashworth
R G
RG
Ahier
S P
SP
Hume
D000818:Animals; D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002230:Carbidopa / Q000494:pharmacology; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000502:physiology*; D004298:Dopamine / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005917:Globus Pallidus / Q000187:drug effects / Q000502:physiology; D006834:Hydrazines / Q000494:pharmacology; D007700:Kinetics; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000502:physiology*; D012457:Salicylamides / Q000378:metabolism; D013997:Time Factors; D014055:Tomography, Emission-Computed; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D065105:Aromatic Amino Acid Decarboxylase Inhibitors; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D006834:Hydrazines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D020891:Raclopride; D007980:Levodopa; D005680:gamma-Aminobutyric Acid; C004297:3-hydroxybenzylhydrazine; D002230:Carbidopa; D004298:Dopamine