Cocaine-seeking by rats: regulation, reinforcement and activation

Rationale: In animal models of drug self-administration, response rates often decrease with dose suggesting that a regulative process may mask the reinforcing effects of the drug. Objective: The purpose of the present experiments was to dissociate the role of regulative and reinforcement processes in intravenous cocaine self-administration by rats using a paradigm that explicitly distinguishes between drug-seeking and drug-taking. Methods: Rats were trained to respond for intravenous cocaine (0.25 mg/infusion) under a heterogeneous chain (tandem FR1 RI 30 s) FR1 schedule of reinforcement using different levers in the first (seeking) and second (taking) links of the chain. After 10 days of training, rats were switched to one of three doses of cocaine (0.08, 0.25, or 0.5 mg/infusion) and self-administration patterns were recorded for a further ten sessions in experiment 1. In experiment 2, a time-out (TO) period (0, 4, or 12 min) was imposed between successive cycles of the chain schedule. Finally, the effect of allowing animals to per form a drug-taking response on subsequent drug-seeking was assessed in experiment 3. Results: Having verified that seeking responses for a conventional reinforcer (sucrose) were sensitive to changes in reward magnitude, experiment 1 demonstrated that the number of self-administered infusions was inversely related to dose whereas the latency to initiate drug-seeking increased with dose. Variations in the cocaine dose had no reliable effect on the number of drug seeking response per cycle of the chain schedule. The effect of dose on the latency to initiate drug-seeking was reversed in experiment 2 with increasing TO periods. Moreover, at the longest TO period, drug-seeking responses per cycle increased and the latency to initiate drug seeking decreased with dose. Experiment 3 showed that the latency to drug-seek for the low dose was reduced dramatically when the first drug-seeking response was preceded by a drug-taking response, even when this response did not produce a drug infusion. Conclusions: The overall pattern of results suggests that drug-seeking and drug-taking are controlled by three interacting processes: a regulative process depresses drug-seeking in the short-term; behavioral activation enhances drug-seeking and is sustained over longer intervals by higher drug doses; the reinforcing effect of cocaine increases with dose once the satiety producing effects of the drug dissipate.