D1/D2 actions of dopaminergic drugs studied with [14C]-2-deoxyglucose autoradiography.
1. To define the neural circuits activated by dopaminergic stimulation in rat models of parkinsonism, the author studied the effects of L-dopa and selective D1 and D2 agonists on RCGU in rats with unilateral 6-OHDA substantia nigra lesions. 2. Systemic administration of L-dopa markedly increased RCGU in the EP and SNr ipsilateral to the nigral lesions; it is suggested that this represents metabolic activity primarily in axon terminals of GABAergic striatal projection neurons. These effects were reproduced by selective D1, but not D2, dopamine agonists, and were blocked completely by a D1 antagonist, indicating their critical dependence on D1 stimulation. L-dopa moderately increased RCGU in the STN; this effect was reproduced by D1 and D2 agonists and was blocked completely only by combined D1 and D2 antagonist pretreatment. 3. The RCGU data support a direct stimulatory action of dopamine, formed from L-dopa, on D1 receptor-bearing striatal GABAergic neurons projecting to the EP and SNr as well as a net stimulatory action on the GP output to the STN. 4. The marked D1-mediated RCGU increase in the SNr ipsilateral to the dopamine depletion contrasts with the modest increase seen on the contralateral side and in naive rats, suggesting that the enhanced RCGU response to D1 stimulation is an index of dopaminergic supersensitivity. The stimulatory effect of the D1 agonist SKF 38393 on RCGU in the SNr is enhanced 6-12 hours after acute dopamine depletion with reserpine/AMPT indicating that supersensitive responses develop within this rapid time frame. 5. The RCGU data indicate that D1 receptor stimulation contributes importantly, in an anatomically selective manner, to the effects of L-dopa on basal ganglia circuits and that the response to D1 stimulation is rapidly modifiable by dopamine depletion.
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville, USA.
J M
JM
Trugman
D000818:Animals; D001345:Autoradiography; D003847:Deoxyglucose / Q000378:metabolism* / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*
D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D003847:Deoxyglucose