Abstract

Dopamine agonists and antagonists varying in affinity and selectivity at the D3 subtype of D2-like receptors were studied in squirrel monkeys trained to discriminate cocaine from vehicle in a two-lever choice procedure. In drug substitution experiments, all dopamine agonists engendered dose-related increases in the percentage of cocaine-lever responses, reaching average maxima of 61 to 85%. The order of potency of the drugs for engendering cocaine-like stimulus effects [(+)-4-propyl-9-hydroxynaphthoxazine > (R)-(-)-propylnorapomorphine > (+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene > or = PD 128907 > or = quinpirole > bromocriptine] approximated their reported order of potency in both functional (agonist-stimulated mitogenesis) and radioligand ([125I]iodosulpiride) binding assays in cells expressing cloned human D3 receptors but not in cells expressing cloned human D2 or D4 receptors. In antagonism studies, the cocaine-like stimulus effects of the most selective of the D3 agonists, PD 128907, were attenuated by D2-like receptor antagonists with an order of potency (nemonapride > eticlopride > YM-43611) that correspondence more closely to their reported order of affinity at cloned human D3 than either D2 or D4 receptors. The effects of PD 128907 were not attenuated by the D1-like receptor antagonist SCH 39166. In a final series of experiments, the discriminative stimulus effects of cocaine were enhanced in a largely additive manner by PD 128907, (+/-)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphthalene and quinpirole. The results support a role for D3 receptor mechanisms in the cocaine-like stimulus effects of D3-preferring agonists and suggest the similar mechanisms may contribute to the effects of cocaine.