D1-D2 INTERACTION IN FEEDBACK-CONTROL OF MIDBRAIN DOPAMINE NEURONS

Dopamine (DA) D1-like receptors are present in pathways implicated in feedback control of midbrain DA neurons. However, stimulation of these receptors either produces no effect on DA cells, or the effect is inc onsistent. It is possible that the expression of a D1 feedback effect requires co-activation of D2-like receptors. To test this hypothesis, we recorded extracellularly the spontaneous activity of nigral DA cell s in a low cerveau isole rat preparation. SKF38393 and dyhydrexidine, two D1 agonists, were administered systemically to animals pretreated with different doses of the D2 agonist quinpirole. Supporting the hypo thesis, the two D1 agonists consistently inhibited DA cells in animals given high doses of quinpirole (greater than or equal to 40 mu g/kg, i.v.). However, no significant D1 effect was observed in animals pretr eated with only low doses (less than or equal to 20 mu g/kg) of quinpi role. Because low doses of D2 agonists preferentially act on DA autore ceptors, and because the D1 inhibition persisted in animals whose DA a utoreceptors were blocked by intranigral application of raclopride, ou r results suggest that the expression of D1 feedback inhibition requir es co-activation of D2-like receptors on DA target neurons, instead of DA neurons themselves. These results, together with the finding that chloral hydrate completely blocked the D1 inhibition, may explain why previous studies have failed to show a consistent D1 effect on DA cell s and suggest that drugs designed to act specifically on one subtype o f DA receptor may, via feedback pathways, influence the action of endo genous DA on other DA receptor subtypes as well.