The D2 family of dopamine (DA) receptors is known to play an important role in the psychostimulant effects of cocaine. Less is known, however, about the contribution of different receptor subtypes (D2, D3, D4) within this family. In the present study, DA agonists differing in affinity and selectivity at the D3 receptor subtype were compared with reference D2 agonists for effects on schedule-controlled behavior in squirrel monkeys. Monkeys were trained to respond under a fixed-interval schedule of stimulus-shock termination shown previously to be sensitive to the stimulant effects of traditional D2 agonists as well as indirect DA agonists such as cocaine and amphetamine. In the majority of monkeys tested, the preferential D3 agonists PD 128,907, R-(+)-7-OH-DPAT, quinelorane, and quinpirole produced dose-related increases in response rate, with maximal effects comparable to those produced by the reference D2 agonists R-(-)-NPA and N-0434. The relative potencies of the D3 agonists for increasing response rate approximated their relative potencies reported in functional (stimulation of [3H]thymidine incorporation) and, to a lesser extent, radioligand binding assays (inhibition of [125I]iodosulpiride binding) in transfected cells expressing hD3 receptors. In contrast, the relative potencies of the reference D2 agonists [R-(-)-NPA about 40 times more potent than N-0434 approximated the relative potencies of these drugs reported in [125I]iodosulpiride binding assays in transfected cells expressing hD2, but not hD3, receptors. The results suggest a role for both the D2 and D3 receptor subtypes in mediating the stimulant effects of DA agonists and suggest that these mechanisms also may contribute to the effects of cocaine.
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