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 critic al role in the mediation of the behavioral effects of cocaine. The pre sent experiments were designed to examine the effects of the glycine-s ite partial agonist (+)-HA966, a compound modulating NMDA receptor fun ction, on the development of sensitization the locomotor activating ef fects of cocaine and on intravenous cocaine self-administration. After chronic cocaine pretreatment (20 mg/kg i.p. daily for 3 days), Spragu e-Dawley rats showed much greater increases in activity after a cocain e challenge (20 mg/kg i.p.) than did saline-pretreated controls. This sensitized response was diminished by (+)-HA966 (30, 100 and 200 mu g) , when administered intraventricularly (i.c.v.) 5 min before each of t he three cocaine pretreatment injections. (+)-HA966 when given alone f or 3 days did not significantly diminish subsequent cocaine-induced lo comotor activity. However, a small dose of (+)-HA966 (30 mu g) potenti ated the acute stimulatory effects of cocaine on locomotor activity; h igher doses were without effect. With limited daily access to intraven ous cocaine (0.33 mg/kg/infusion), rats showed reliable patterns of se lf-administration under a fixed-ratio 3 (FR3) schedule of reinforcemen t. Pretreatment with small doses of (+)-HA966 administered 5 min prior to cocaine self-administration sessions had little effect. However, l arger doses (100 and 200 mu g i.c.v.) significantly decreased respondi ng. This effect was selective, since similar doses produced significan tly less suppression of operant responding for food. The non-competiti ve NMDA receptor antagonist, dizocilpine (0.03-0.3 mg/kg i.p.) adminis tered 30 min prior to sessions, significantly decreased cocaine self-a dministration without modifying behavior maintained by food. The prese nt findings demonstrate that modulation of NMDA systems can significan tly modify the behavioral effects of cocaine.