PRECLINICAL STUDY: Stimulation of 5‐HT1Breceptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

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Abstract
Paradoxically, stimulation of 5‐HT1Breceptors (5‐HT1BRs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/reinstatement model. We revisited this issue by examining the effects of a 5‐HT1BR agonist, CP94253, on cocaine reinforcement and cocaine‐primed reinstatement, predicting that CP94253 would enhance cocaine‐seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self‐administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine‐seeking behavior (operant responses without cocaine reinforcement). Next, they were pre‐treated with CP94253 (3–10 mg/kg, s.c.) and either tested for cocaine‐primed (10 or 2.5 mg/kg, i.p.) or cue‐elicited reinstatement of extinguished cocaine‐seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self‐administered cocaine doses (0–1.5 mg/kg, i.v.) were examined. Cocaine dose‐dependently reinstated cocaine‐seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue‐elicited reinstatement. In contrast, CP94253 shifted the self‐administration dose‐effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine‐seeking behavior). In subsequent control experiments, CP94253 decreased open‐arm exploration in an elevated plus‐maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5‐HT1BRs produces opposite effects on cocaine reinforcement and cocaine‐seeking behavior, and further suggest that 5‐HT1BRs may be a novel target for developing medications for cocaine dependence.