Behavioral studies with the glycine partial agonist (+)-HA966 on cocaine-induced locomotor activity and reinforcement.

Recent evidence suggests that excitatory amino acids may play a critical role in the mediation of the behavioral effects of cocaine. The present experiments were designed to examine the effects of the glycine-site partial agonist (+)-HA966, a compound modulating NMDA receptor function, on the development of sensitization the locomotor activating effects of cocaine and on intravenous cocaine self-administration. After chronic cocaine pretreatment (20mg/kg i.p. daily for 3 days), Sprague-Dawley rats showed much greater increases in activity after a cocaine challenge (20mg/kg i.p.) than did saline-pretreated controls. This sensitized response was diminished by (+)-HA966 (30, 100 and 200µg), when administered intraventricularly (i.c.v.) 5min before each of the three cocaine pretreatment injections. (+)-HA966 when given alone for 3 days did not significantly diminish subsequent cocaine-induced locomotor activity. However, a small dose of (+)-HA966 (30µg) potentiated the acute stimulatory effects of cocaine on locomotor activity; higher doses were without effect. With limited daily access to intravenous cocaine (0.33mg/kg/infusion), rats showed reliable patterns of self-administration under a fixed-ratio 3 (FR3) schedule of reinforcement. Pretreatment with small doses of (+)-HA966 administered 5min prior to cocaine self-administration sessions had little effect. However, larger doses (100 and 200µg i.c.v.) significantly decreased responding. This effect was selective, since similar doses produced significantly less suppression of operant responding for food. The non-competitive NMDA receptor antagonist, dizocilpine (0.03-0.3mg/kg i.p.) administered 30min prior to sessions, significantly decreased cocaine self-administration without modifying behavior maintained by food. The present findings demonstrate that modulation of NMDA systems can significantly modify the behavioral effects of cocaine.