Excitatory amino acid (EAA) neurotransmitters may play an important role in conditioning associations between psychomotor stimulant drug effects and environmental stimuli. This role for EAAs has been indicated by recent studies showing that the non-competitive NMDA receptor antagonist, MK-801, can block the development of conditioned locomotor activity produced when amphetamine is repeatedly given to rats in a specific environment. The experiments proposed here will characterize the EAA mechanisms underlying the conditioning of cocaine's locomotor activating effects by determining the extent to which NMDA and non-NMDA EAA receptors are involved, and by specifying the locations of these receptors within the CNS. The involvement of NMDA and non-NMDA EAA receptors in the development of conditioned activity produced with cocaine will be investigated by pretreating rats intracerebroventricularly (icv) with several doses of the competitive NMDA receptor antagonists AP5 and CPP, and the non-NMDA receptor antagonists CNQX and NBQX prior to pairing cocaine injections with specific environmental stimuli. The ability of these antagonists to block the expression of conditioned activity also will be assessed by giving the compounds prior to cocaine-free activity tests in the conditioning environment. CNS regions involved in the development and expression of cocaine- conditioned activity will be identified using technique for mapping the expression of immediate early gene products (Fos, Jun and NGFI-A). Immediate early gene (IEG) products also will be mapped in rats that were pretreated (icv) with NMDA and non-NMDA EAA antagonists prior to pairing sessions or conditioning tests. Regions where the expression of IEGs by cocaine or cocaine-paired stimuli is prevented may be sites where the antagonists act to interfere with the development or expression of conditioning. Behavioral experiments will assess the involvement of these regions in mediating the effects of EAA antagonists on cocaine conditioning by injecting the NMDA and non-NMDA antagonists directly into the sites prior to conditioning sessions or tests for conditioned activity. Particular attention will be paid to the possible involvement of the amygdala and the nucleus accumbens. These regions have been implicated in the conditioning of motivational responses and they contain high densities of glutamate receptors. These experiments will advance our understanding of the EAA mechanisms involved in the conditioning of associations between environmental stimuli and psychomotor stimulant drug effects. The results of these studies will provide important information concerning the type and location of EAA receptors involved in this conditioning, and they will suggest new avenues for the development of pharmacological treatments to control the elicitation of drug cravings by environmental stimuli.
