Effects on cocaine and food self-administration of (+)-HA-966, a partial agonist at the glycine/NMDA modulatory site, in rats.

(+)-HA-966, a partial agonist at the glycine/NMDA modulatory site, significantly reduced i.v. cocaine self-administration in a fixed-ratio (FR) schedule. Since this effect was observed studying only one dose of cocaine and considering the characteristic bell-shaped curve generated by cocaine in self-administration studies under FR schedules, the precise nature of the effect is not clear. To identify the nature of the effect of (+)-HA-966 on cocaine self-administration under fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. Rats were prepared with i.v. catheters and trained to self-administer cocaine. In the first experiment three doses of (+)-HA-966 (10, 30 and 100 microg/5 microl i.c.v.) were evaluated for their effects on 0.25 mg/0.1 ml per infusion cocaine self-administration on FR1 with 20-s time-out (TO). Next, 30 microg/5 microl i.c.v. (+)-HA-966 was evaluated as pretreatment on a complete dose-response for cocaine self-administration. In a third experiment the effect of the same dose was evaluated on cocaine or food self-administered on the PR schedule. (+)-HA-966 at doses of 10 or 30 microg reduced cocaine self-administration in an FR1 schedule during the first hour interval of the 2-h session. This partial agonist at the glycine/NMDA modulatory site also reduced the number of injections of cocaine earned during the first hour of the session but not the final ratio reached under a PR schedule. However, under this schedule (+)-HA-966 also reduced operant responding for food reinforcement. (+)-HA-966 reduced responding maintained by cocaine or food. Whether (+)-HA-966 induces a general motivational rather than a performance deficit, leading to reduced responding for either cocaine and food, is unclear.