Longitudinal analysis of changes in nucleus acumbens reward processing across protracted cocaine self-administration

Theories suggest that drug dependence develops as drug use transitions from acute ingestion to protracted drug-taking behavior. Studies in both humans and primates have shown that striatal circuitry is intimately involved in these long term changes. Notably, the ventromedial portion of the striatum (i.e., the nucleus accumbens) has a long established role in supporting the reinforcing properties of abused drugs and in modulating drug-seeking behaviors. To date, however, a thorough longitudinal analysis of the functional changes in accumbens activity during the transition from acute to chronic drug use has yet to be conducted. Thus, the goal of the present experiment was to track single neuron activity across 24 days of chronic, long-access (6 hours/day) self-administration training and examine changes in the tonic firing patterns of accumbens neurons as well as changes in firing patterns during on-drug locomotion, approach to the operant, and operant responding. Finally, the relationship between drug level and firing rate was examined longitudinally. To accomplish this, animals were shaped and iii subsequently trained to self-administer cocaine by performing an operant head movement on a variable-interval schedule. Single-units were recorded across self-administration sessions using an array targeting the nucleus accumbens core and shell. Data recorded from wires that had been localized to the accumbens core, shell, or core/shell border using antibodies raised against Calbindin D28-K were then analyzed longitudinally using a generalized linear model. Results from the present study establish that continued cocaine use corresponds to stable negative correlations between drug level and the firing rates of accumbens neurons. Moreover, dynamic changes in the firing patterns of accumbens neurons during operant responding were observed over sessions. In contrast, firing during locomotor behaviors and goal-directed approaches was not different from baseline firing rates. Overall these results suggest that the accumbens plays a specific role in response-reinforcement learning and may exhibit plastic changes in firing patterns as learning occurs. Moreover, the strength of learned associations may be influenced by the effects of cocaine, which produces a robust effect on accumbens neurons, even upon first exposure.Ph. D.Includes bibliographical referencesby David James Barke