D1/D2 dopamine receptor stimulation by L-dopa. A [14C]-2-deoxyglucose autoradiographic study.
In rats with unilateral 6-hydroxydopamine substantia nigra lesions, the effects of selective D1 and D2 dopamine receptor antagonists on L-DOPA-induced rotation and regional cerebral glucose utilization (RCGU) changes were examined. Contralateral rotation induced by L-DOPA (25 mg/kg) was effectively blocked by D1 (SCH 23390, 1.0 mg/kg) and D2 (eticlopride, 2.0 mg/kg) antagonists, in combination, but not by either antagonist alone. This suggests that in the dopamine-depleted rat, L-DOPA administration results in the stimulation of both D1 and D2 receptor systems, each capable of independently eliciting a full motor response, L-DOPA altered RCGU in the following brain regions ipsilateral to the lesion: entopeduncular nucleus (EP, + 105%), substantia nigra pars reticulata (SNr, + 121%), subthalamic nucleus (STN, + 32%), deep layers of the superior colliculus (DLSC, + 35%), and lateral habenula nucleus (LHN, -52%). The effects in the EP and SNr were blocked completely by D1 antagonist pretreatment but only partially attenuated by D2 antagonist pretreatment, indicating the critical dependence of these changes on D1 stimulation. In contrast, combined D1 and D2 antagonist pretreatment, but neither drug alone, blocked the L-DOPA-induced increases in the STN and DLSC. The effects of L-DOPA in the LHN were attenuated by either SCH 23390 or eticlopride, and blocked completely by the antagonist combination. These results provide evidence that dopamine formed following the decarboxylation of L-DOPA stimulates both D1 and D2 receptors in vivo and that stimulation of each receptor contributes uniquely to its physiological effects. Neural mechanisms of action of L-DOPA are discussed in the context of these findings.
Trugman
J M
JM
Department of Neurology, University of Virginia School of Medicine, Charlottesville 22908.
James
C L
CL
Wooten
G F
GF
D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003847:Deoxyglucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D008959:Models, Neurological; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides / Q000494:pharmacology
D001552:Benzazepines; D002250:Carbon Radioisotopes; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D007980:Levodopa; D003847:Deoxyglucose; D005947:Glucose; C045989:eticlopride