The GABA_B antagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat

Abstract.

Rationale: Several reports have demonstrated that the γ-aminobutyric acid (GABA)_B agonist baclofen attenuates the reinforcing effects of cocaine in rats, and recent evidence indicates that it might have a similar effect on heroin self-administration. Objectives: The specific GABA_B receptor antagonist CGP56433A was used to further evaluate the involvement of GABA_B receptors in the baclofen-induced suppression of cocaine and heroin self-administration. Methods: In the first series of experiments, dose–response curves were generated to examine the effect of CGP56433A (0.6, 1.0, or 1.8 mg/kg, i.p.) on cocaine (1.5 mg/kg per injection) and heroin (25 µg/kg per injection) self-administration reinforced under a fixed-ratio (FR1) or progressive ratio (PR) schedule. Separate sets of experiments then examined the effect of the co-administration of CGP56433A and baclofen on responding for cocaine or heroin under both schedules. Results: Pretreatment with CGP56433A had no effect on cocaine or heroin self-administration, while baclofen dose dependently reduced responding for both cocaine and heroin under both the FR1 and PR schedule. CGP56433A (1.8 mg/kg) blocked the effect of baclofen on cocaine but not on heroin self-administration. Conclusion: The specific GABA_B antagonist CGP56433A attenuated the effect of baclofen on cocaine self-administration, suggesting that GABA_B receptors are critical in mediating the anti-cocaine effect of baclofen. In combination with other studies, the data demonstrate that the susceptibility of baclofen and other GABA_B agonists to receptor blockade depends on the behavioral response being studied. Whether this indicates different receptor mechanisms are involved (e.g., pre- versus post-synaptic effects or differential receptor reserve) remains to be determined.