Our lab has previously established that adult outbred Sprague-Dawley rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) following an acute low dose of cocaine. With repeated cocaine, LCRs, more than HCRs, develop locomotor sensitization, conditioned place preference (CPP), and motivation to self-administer cocaine, suggesting a vulnerability to the activating, rewarding, and reinforcing effects of cocaine. Increased cocaine-induced inhibition of the dopamine (DA) transporter in the nucleus accumbens (NAc) of LCRs, but not HCRs, after repeated cocaine, parallels the development of locomotor sensitization in LCRs. Differences in other neurotransmitters like glutamate could also help to explain why LCRs, more than HCRs, develop repeated cocaine locomotor sensitization and CPP. Repeated cocaine-induced increases in extracellular glutamate in NAc, as well as changes in glutamate receptor (GluR) subunits in the ventral tegmental area (VTA) and NAc, are seen only in rats that develop locomotor sensitization to cocaine. Because LCRs and HCRs differ in mesoaccumbens DA responses to cocaine, and it is known that glutamate influences DA neurotransmission in the dorsal striatum (dSTR), VTA and NAc, my specific aims are: 1. Determine potential differences between LCRs and HCRs in basal and cocaine-induced GluR subunit expression, along with changes in locomotor activity. 2. Compare cocaine-induced changes in locomotor activity and extracellular glutamate levels in the NAc of LCRs and HCRs. 3. Examine the role of NMDARs in development of locomotor sensitization and CPP in LCRs and HCRs. These aims will use biochemical and behavioral approaches to test the hypothesis that the response of glutamate systems to acute and repeated cocaine differs between LCRs and HCRs. GluR subunit expression will be assessed in the dSTR, NAc, and VTA using cell surface assays and western blot techniques. Extracellular glutamate will be measured in the NAc using in vivo microdialysis concurrently with locomotor activity measurements in the open field. The role of NMDARs in the development of locomotor sensitization and CPP will be assessed using an NMDAR antagonist locally delivered into the VTA while measuring cocaine-induced locomotor activity and development of CPP. PUBLIC HEALTH RELEVANCE: Glutamate is critical for learning and memory processes involved in the development of addiction. Because individuals vary in their susceptibility to addiction, it is important to better understand individual differences in glutamate system response to cocaine with the goal of finding new molecular targets for treatments.