Intermittent Cocaine Use Patterns, Not Total Intake, Predict Cue-induced Drug Seeking in Rats

Background and purposeCocaine-associated cues trigger relapse to drug use in humans and animal models. In rats, long daily cocaine access (4-6 h vs. 1-2 h) increases drug self-administration and cue-induced cocaine seeking, suggesting that greater intake promotes relapse. However, prior studies used continuous-access paradigms, whereas human cocaine use is typically intermittent. Moreover, these studies used conditioned stimuli (CS), whereas discriminative stimuli (DS) are more effective in triggering increases in drug-seeking actions. Here, we used intermittent access (IntA) self-administration to examine how session length (Short-IntA: 2 h vs. Long-IntA: 4 h) affects CS- and DS-induced cocaine seeking. Experimental approachFemale rats self-administered cocaine intermittently during daily 2- or 4-h IntA sessions, with alternating DS+ (cocaine available; 5 min) and DS- (no cocaine; 25 min) periods. Lever pressing during DS+ delivered cocaine and a CS+; lever pressing during DS-delivered only a CS-. After four weeks of abstinence, rats received a cocaine-seeking test where all cues were presented response-independently, and lever presses - which had no consequence - measured cocaine seeking. Key resultsLong-IntA rats took twice more cocaine than did Short-IntA rats. Both groups later showed significant (DS+)-but not (CS+)-triggered cocaine seeking, with no group differences. Thus, total intake did not predict cue-induced relapse propensity. However, individual cocaine intake patterns did (hourly consumption, burst-like self-administration, and latency to first infusion). Conclusions and ImplicationsUnder intermittent-access conditions, individual cocaine-use patterns, not cumulative intake, predict vulnerability to cue-induced relapse. This highlights the importance of individual drug-taking profiles in relapse risk assessment.