Neuropharmacology 38 (1999) 1797 – 1804 The GABA B agonist CGP 44532 decreases cocaine self-administration in rats: demonstration using a progressive ratio and a discrete trials procedure Karen Brebner a , Wolfgang Froestl b , Monique Andrews a , Rachel Phelan a , David C.S. Roberts a, * a Life Sciences Research Centre, Carleton Uniersity, Ottawa, Ontario, Canada b NOVARTIS Pharma AG, CH-4002, Basel, Switzerland Accepted 24 May 1999 Abstract Previous self-administration experiments have shown that baclofen, the prototypical GABA B agonist, produces an apparent attenuation in the reinforcing effects of cocaine in rats. The present experiments examined the effects of CPG 44532, a novel and highly specific GABA B agonist, on cocaine self-administration using two distinctly different procedures. CGP 44532 (0.063 – 0.5 mg/kg) produced a dose dependent decrease in break point on a progressive-ratio (PR) schedule. A low dose of CGP 44532 (0.125 mg/kg) produced an apparent shift of the cocaine dose – response curve to the right. In contrast there was comparatively little effect on food-reinforced responding on the same PR schedule. Using a discrete-trials procedure that engendered a circadian pattern of self-administration, CPG 44532 (0.063 – 0.5 mg/kg) produced a dose-dependent suppression of cocaine intake in the 4 h period following treatment. When a concurrently available food reinforced lever was added to the discrete trials paradigm CGP 44532 failed to disrupt responding for food at any of the doses tested. Data from the PR and discrete-trials procedures taken together indicate that CGP 44532 produced a specific decrease in the motivation to self-administer cocaine. © 1999 Elsevier Science Ltd. All rights reserved. Keywords: GABA; Self-administration; CGP 44532; Progressive ratio; Discrete trials; Cocaine www.elsevier.com/locate/neuropharm 1. Introduction Animal models have provided considerable evidence to indicate that the mesocortical-mesolimbic dopamine (DA) system is critically involved in cocaine reinforce- ment (Koob, 1992; Roberts, 1992; Woolverton and Johnson, 1992), and it has been suggested that a pro- gressive dysregulation of reward circuits within this system following prolonged or compulsive drug use may be involved in vulnerability to addiction and to relapse in humans (Koob, 1996; Koob et al., 1998). However, clinical trials with dopamine agonists or an- tagonists have not resulted in the development of an effective medication that promotes abstinence from co- caine use. Despite some promising reports from open trials, double blind studies have generally failed to confirm significant therapeutic effects (Kleber, 1995). A variety of physiological and neurochemical data indicate that DA and GABA systems are intimately associated. GABA B receptor stimulation has been shown to markedly inhibit firing of dopaminergic cells (Kalivas, 1993) and to decrease dopamine release (Bow- ery et al., 1980; Klitenick et al., 1992; Santiago et al., 1993; Yoshida et al., 1994). These data suggest that GABA drugs are capable of specifically modulating DA dependent behaviors, although the effect of GABA compounds on cocaine self-administration have thus far received little attention. We have recently shown that baclofen, a GABA B agonist, produces an appar- ently selective decrease in the motivation of rats to self-administer cocaine. This was demonstrated using * Corresponding author. Present address: Department of Physiol- ogy and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA. Tel.: +1-336-716-8597; fax: +1-336-716-8501. E-mail address: dcsrobts@wfubmc.edu (D.C.S. Roberts) 0028-3908/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(99)00094-5