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 ef- fect on heroin self-administration. Objectives: The spe- cific GABA B receptor antagonist CGP56433A was used to further evaluate the involvement of GABA B receptors in the baclofen-induced suppression of cocaine and hero- in self-administration. Methods: In the first series of ex- periments, dose–response curves were generated to ex- amine 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-adminis- tration. 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 baclo- fen. In combination with other studies, the data demon- strate that the susceptibility of baclofen and other GABA B agonists to receptor blockade depends on the behavioral response being studied. Whether this indi- cates different receptor mechanisms are involved (e.g., pre- versus post-synaptic effects or differential receptor reserve) remains to be determined. Keywords CGP56433A · Baclofen · Cocaine · Heroin · GABA · Agonist · Self-administration Introduction A growing body of evidence indicates that cocaine rein- forcement can be modulated by stimulation of γ-amino- butyric acid B (GABA B ) receptors. Several recent studies have reported that GABA B agonists such as baclofen and CGP44532 produce a robust modulation of cocaine self- administration under several different schedules of rein- forcement (Roberts et al. 1996; Roberts and Andrews 1997; Shoaib et al. 1998; Brebner et al. 1999, 2000a, 2000b; Campbell et al. 1999; see Roberts and Brebner 2000 for review). While GABA B receptors are widely distributed throughout the brain (Bischoff et al. 1999; Billinton et al. 2000), several lines of evidence support the hypothesis that GABA B receptors on dopamine (DA) neurons within the ventral tegmental area (VTA) are crit- ical in mediating baclofen’s anti-cocaine effect. Microin- jections of baclofen into the VTA have been shown to have direct effects on DA pathways, causing a decrease in the release of extracellular DA in the nucleus accumb- ens (NAC) (Kalivas et al. 1990; Kalivas 1993; Yoshida et al. 1994; Westerink et al. 1997). Evidence for a specif- ic role for the VTA in the behavioral effects of cocaine has been suggested by the finding that intra-VTA baclo- fen prevents the motor-stimulant responses to peripheral cocaine (Kalivas et al. 1990) and selectively reduces co- caine self-administration under fixed ratio (FR; Shoaib et al. 1998) and progressive ratio (PR) schedules of rein- forcement (Brebner et al. 2000b). Antagonists for specific receptor subtypes are often used to help define and confirm the mechanisms associ- K. Brebner · D.C.S. Roberts ( ✉ ) Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1083, USA e-mail: dcsrobts@wfubmc.edu Tel.: +1-336-7168597, Fax: +1-336-7168501 W. Froestl Therapeutic Area Nervous System, Novartis Pharma AG, Basel, Switzerland K. Brebner Department of Psychiatry, University of British Columbia, Vancouver, Canada Psychopharmacology (2002) 160:49–55 DOI 10.1007/s00213-001-0952-7 ORIGINAL INVESTIGATION Karen Brebner · Wolfgang Froestl · David C. S. Roberts The GABA B antagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat Received: 30 April 2001 / Accepted: 2 October 2001 / Published online: 18 December 2001 © Springer-Verlag 2001