Dopamine D-3 receptor agonists partially reproduce the discriminative stimulus effects of cocaine in squirrel monkeys

Dopamine agonists and antagonists varying in affinity and selectivity at the D-3 subtype of D-2-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 greater than or equal to PD 128907 greater than or equal to quinpirole > bromocriptine] approximated their reported order of potency in both functional (agonist-stimulated mitogenesis) and radioligand ([I-125]iodosulpiride) binding assays in cells expressing cloned human D-3 receptors but not in cells expressing cloned human D-2 or D-4 receptors. In antagonism studies, the cocaine-like stimulus effects of the most selective of the D-3 agonists, PD 128907, were attenuated by D-2-like receptor antagonists with an order of potency (nemonapride > eticlopride > YM-43611) that corresponded more closely to their reported order of affinity at cloned human D-3 than either D-2 or D-4 receptors, The effects of PD 128907 were not attenuated by the D-1-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 D-3 receptor mechanisms in the cocaine-like stimulus effects of D-3-preferring agonists and suggest that similar mechanisms may contribute to the effects of cocaine.