This revised FIRST Award application focuses on the neurobiological basis of nucleus accumbens (NA) cell firing during cocaine self-administration and water reinforcement sessions in rats. In accordance with reviewer suggestions it no longer attempts to propose this research as a specific """"""""model"""""""" of human drug craving (NIH Guide, Vol 23, Num 41, 11/25/94). We have previously demonstrated that a subset of NA neurons exhibit 3 types of patterned discharges relative to both cocaine and water reinforced responding in rats (Carelli et al., 1993; Carelli and Deadwyler, 1994). An important feature of NA cell firing in both reinforcer conditions was the temporal specificity and complimentary manner in which these cell types discharged during behavioral performance. These findings suggest that distinct features of the reinforced behavior are """"""""encoded"""""""" by different neurons in the NA. However, no information exists regarding mechanisms which control the differential discharge patterns of NA neurons in this context. Four studies are proposed to provide critical information regarding the basis of this patterned firing of NA cells with respect to the intrinsic (local) circuitry of the NA, and the influence of cells which give rise to NA afferents within this local circuit as recorded in behaving animals. Exp. I is designed to characterize the local circuitry of the NA by examining the activity of the same NA cell during both cocaine and water reinforcement sessions with respect to their distribution within 3 subregions (core, shell and rostral pole) of the NA of the rat. Exp. 2 is designed to examine the influence of cells which give rise to particular NA afferents on the activity of NA cells within the intrinsic circuit determined in Exp. 1. This will be accomplished by comparing identified NA cell firing with neural activity simultaneously recorded from subregions of the subiculum, amygdala and prefrontal cortex during cocaine self-administration and water reinforcement sessions. Information gained from these studies will be applied to Exps. 3 and 4 to examine mechanisms controlling dynamic properties of NA cell firing. Exp. 3 will examine possible mechanisms underlying the documented spontaneous transitions in NA cell firing during cocaine self-administration sessions in rats. Since transitions in NA cell firing and behavioral responding appear to depend upon cocaine induced elevations of dopamine in the NA, the role of dopamine within this process will be determined via pharmacological manipulation of dopamine D, and D2 receptors. Exp. 4 will determine factors which mediate the associative properties of NA cell firing. These studies will provide information regarding the functional organization of the NA and its role in reward mechanisms in the behaving animal. Results will be directly relevant to understanding the neurobiological basis of conditioned drug effects reported to be a major contributor to problems in human drug abusers (O'Brien et al., 1992).
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