Reinforcing effects of D2 dopamine receptor agonists and partial agonists in rhesus monkeys

Dopamine (DA) receptors play a role in the reinforcing effects of psychomot or stimulants and other drugs. Both DI and D2 DA receptor agonists have bee n reported to function as positive reinforcers in maintaining self-administ ration in non-human subjects. The purpose of the present study was to evalu ate. in monkeys, the reinforcing effects of DA D2 receptor agonists that va ry in their efficacy as D2 agonists. Rhesus monkeys were prepared with veno us catheters and lever pressing was maintained by i.v. cocaine (n = 5, 0.03 mg/kg/inj) in daily baseline sessions (2 h/day, fixed ratio 25). Various d oses of cocaine or D2 agonists were then made available for at least four t o seven sessions, and until responding was stable. At least one dose of the higher-efficacy D2 agonists, R(-)-propylnorapomorphine (NPA) (n = 4, 0.001 -0.01 mg/kg/inj), R(-)-apomorphine (APO) (n = 4, 0.003-0.1 mg/kg/inj) and R (+)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl [R(+)-3-PPP] (n = 4, 0.03-0. 3 mg/kg/inj), functioned as a positive reinforcer in all the monkeys tested . In contrast, no dose of the lower-efficacy D2 agonists, R(+)-terguride (n = 4, 0.001-0.3 mg/kg/inj) and S(-)-3-(3-hydroxyphenyl)-N-propylpiperidine HCl [S( -)-3-PPP] (n = 4, 0.001-0.3 mg/kg/inj), maintained self-administrat ion. In in vitro binding studies with monkey brain tissue NPA and terguride had high affinities for the D2 receptor, while APO had intermediate affini ty, and the 3-PPPs had low affinity. Among the compounds that were reinforc ers potency as a reinforcer was directly related to D2 affinity in three of the four monkeys, consistent with D2 receptor involvement in the reinforci ng effect of these compounds. The data suggest that the efficacy at D2 rece ptors is directly related to the reinforcing effect. (C) 2001 Elsevier Scie nce Ireland Ltd. All rights reserved.