Cocaine Self-Administration and Time-dependent Decreases in Prelimbic Activity

ABSTRACT Cocaine self-administration causes dephosphorylation of proteins in prelimbic (PL) cortex that mediate excitation-transcription coupling, suggesting that cocaine causes decreased activity in PL neurons. Thus, we used in vivo single-unit extracellular recordings in awake, behaving rats to measure activity in PL neurons before, during, and after cocaine self-administration on the first and last session day (range 12-14 days). On the last day, cocaine suppressed 52% of recorded neurons in the PL cortex when compared to a 20 min baseline, significantly more than the 23% of neurons suppressed on the first day of cocaine. There was no change in the percentage of neurons that were excited on the first vs. the last day of self-administration (14% vs. 13%, respectively). To determine whether the tonic inhibitory shift was induced by the behavior or by the drug itself, rats received a final session in which cocaine availability was delayed for the first 30 min or in which cocaine was administered non-contingently in the absence of levers or cues in a subset of rats. These manipulations indicated that cocaine was both necessary and sufficient to induce a downshift in PL neuronal activity. However, this activity decrease was not observed in rats that received only non-contingent cocaine for 12-14 days, indicating that contingency during self-administration training contributes to the cocaine-induced tonic downshift in PL activity. These data suggest that the session-by-session decrease in PL neuronal activity induced by cocaine is a reflection of learned drug-seeking behavior and, hence, reducing this inhibition may lessen cocaine addiction.