This is a revised Stage II application written in response to the Program Announcement entitled """"""""Cutting Edge Basic Research Awards"""""""" (PA #: PAR-03-017) designed to foster 'high-risk and potentially high-impact' research that will 'advance our understanding of drug abuse and addiction'. The PI has used electrophysiological recording procedures in behaving rats to investigate underlying cellular mechanisms mediating the reinforcing properties of cocaine. One advantage of this approach is that it enables the characterization of nucleus accumbens (Acb) cell firing at crucial times during goal-directed behaviors (see Carelli, 2002; Appendix A). However, one disadvantage of this approach is that the role of dopamine (DA) in reward-related processing can only be indirectly inferred. In contrast, fast scan cyclic voltammetry (FSCV) can be used to directly measure DA in the Acb on a subsecond time scale with micron spatial resolution that provides chemical information temporally analogous to data obtained from unit recording. In this regard, the PI is working in collaboration with Dr. Mark Wightman, an analytical chemist and pioneer in the development and application of FSCV to behaving animals, and has uncovered changes in DA efflux in the Acb during key aspects of drug-taking behavior. Although informative, we cannot make definitive statements about the precise relationship between Acb cell firing and DA since measurements were completed in different animals (and obviously different sites in the Acb). Therefore, our Stage I application was designed to develop the technology to measure changes in Acb cell firing and Acb dopamine from the same electrode in behaving rats. Now complete, four Specific Aims are proposed here to apply this technology.
Aim 1 will examine corresponding changes in Acb cell firing and DA during cocaine self-administration in rats. The results of Aim 1 will provide unprecedented information concerning whether subsecond changes in DA correlate with Acb activity that encode cocaine-seeking behaviors.
Aim 2 will use the combined technique to determine the contribution of phasic DA to the associative properties of Acb cell firing documented by the PI. This study will provide the first direct evidence that phasic DA may play a role in activating Acb neurons that process information about cocaine-associated stimuli.
Aim 3 will expand information gained in Aims 1 & 2 and examine Acb cell firing and subsecond changes in DA during goal-directed behaviors for 'natural' (water) reinforcement. Finally, Aim 4 will expand information gained above by iontophoretic (local) application of drug in conjunction with the combined technique during self-administration. This study will provide evidence that changes in Acb firing patterns are the result of phasic DA and determine the involvement of specific DA receptors in this process.
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