Attenuation of cocaine-seeking behaviour by the AMPA/kainate receptor antagonist CNQX in rats

Rationale: It has been suggested previously that conditioned effects on drug-seeking behaviour are in part mediated through glutamatergic neurotransmission. Objectives: To optimise a second-order schedule of IV cocaine reinforcement in Wistar rats and investigate the effects of the systemic AMPA/kainate receptor antagonist CNQX on cocaine-seeking behaviour under this schedule. Methods: Free-feeding Wistar rats were trained to respond for an IV cocaine infusion (0.25 mg/infusion) under a FI15 min(FR7:S) schedule, whereby the completion of FR7 responses led to the presentation of a conditioned stimulus (CS). After two 15-min fixed intervals, rats were allowed to respond for cocaine under an FR4(FR7:S) second-order schedule for another 120 min. After acquisition of stable responding, the cocaine unit dose was increased to 0.50 mg/infusion. The effects of CNQX (0, 0.75, 1.5, and 3 mg/kg IP) on cocaine seeking were then examined using a within-subjects design. Results: Increasing the cocaine unit dose increased responding during the first and second intervals, with a decrease in the latency to the first CS. CNQX decreased the number of cocaine responses in a dose-dependent manner during the first 15-min cocaine-free interval, but did not affect cocaine responding during either the second interval or the latter part of the session under the FR4(FR7:S) schedule. In the locomotor activity test, reductions in rearing were produced by higher CNQX doses than those that attenuated significantly responding during the first fixed interval. Conclusions: These results suggest that AMPA/kainate receptors are involved in mediation of cocaine-seeking behaviour controlled partly by cocaine-associated cues.