Distinct subsets of nucleus accumbens (NAc) neurons differentially encode goal-directed behaviors for natural vs. drug rewards [R. M. Carelli et al. (2000)The Journal of Neuroscience, 20, 4255-4266], and the encoding of cocaine-seeking is altered following cocaine abstinence [J. A. Hollander & R. M. Carelli (2007) The Journal of Neuroscience, 27, 3535-3539]. Here, electrophysiological recording procedures were used to determine if the selective encoding of natural vs. cocaine reward by NAc neurons is: (i) maintained when the natural reinforcer is a highly palatable sweet tastant and (ii) altered by cocaine abstinence. Rats (n = 14) were trained on a multiple schedule of sucrose reinforcement and cocaine self-administration (2-3 weeks) and NAc activity was recorded during the task before and after 30 days of cocaine abstinence. Of 130 cells recorded before abstinence, 82 (63%) displayed patterned discharges (increases or decreases in firing rate, termed phasic activity) relative to operant responding for sucrose or cocaine. As in previous reports, the majority of those cells displayed nonoverlapping patterns of activity during responding for sucrose vs. cocaine. Specifically, only 17 (21%) showed similar patterns of activity (i.e. overlapping activity) across the two reinforcer conditions. After abstinence, this pattern was largely maintained, 23 of 70 phasic cells (33%) were overlapping. However, cocaine abstinence altered the overall percentage of selectively active neurons across reinforcer conditions. Specifically, significantly more neurons became selectively activated during cocaine-directed behaviors than during sucrose-directed behaviors. The results indicate that, although the selective encoding of cocaine and natural rewards is maintained even with a highly palatable substance, 30 days of cocaine abstinence dynamically alters the overall population encoding of natural and drug rewards by NAc neurons.