RATIONALE: Previous studies have strongly implicated a role for GABA(B) receptors in modulating the reinforcing effects of cocaine. OBJECTIVE: The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement. METHODS: Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined. RESULTS: On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs. CONCLUSIONS: These findings suggest that positive allosteric modulators of the GABA(B) receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.
RATIONALE: Previous studies have strongly implicated a role for GABA(B) receptors in modulating the reinforcing effects of cocaine. OBJECTIVE: The purpose of the present study was to examine the efficacy of two novel positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to decrease cocaine self-administration in rats responding under various schedules of reinforcement. METHODS:Rats were trained to self-administer cocaine under progressive ratio (PR), fixed ratio (FR) and discrete trials (DT) schedules of reinforcement, and the ability of CGP7930 and GS39783 to decrease cocaine-maintained responding was examined. RESULTS: On a PR schedule, CGP7930 markedly decreased break points maintained by 1.5 mg/kg per injection cocaine in a dose-dependent manner. GS39783 produced only modest decreases in cocaine-reinforced break points, with only the highest dose decreasing break points relative to baseline. On an FR1 schedule of reinforcement, both drugs decreased responding for a threshold dose of cocaine, but did not alter responding for higher doses of cocaine. In a DT procedure, 1.5 mg/kg per injection cocaine was made available during three 10-min trials each hour during 24-h sessions (DT3), engendering a circadian pattern of responding characterized by high numbers of infusions during the dark phase and low numbers of infusions during the light phase. Doses of 30 mg/kg CGP7930, 3.0 mg/kg GS39783 and 2.5 mg/kg baclofen significantly decreased cocaine-maintained responding when administered at the beginning of the dark phase of the cycle. Across all schedules, CGP7930 was more effective at decreasing cocaine self-administration than GS39783, a finding that may be due to differences in bioavailability between the two drugs. CONCLUSIONS: These findings suggest that positive allosteric modulators of the GABA(B) receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.
Authors: S Urwyler; J Mosbacher; K Lingenhoehl; J Heid; K Hofstetter; W Froestl; B Bettler; K Kaupmann Journal: Mol Pharmacol Date: 2001-11 Impact factor: 4.436
Authors: C R Ashby; R Rohatgi; J Ngosuwan; T Borda; M R Gerasimov; A E Morgan; S Kushner; J D Brodie; S L Dewey Journal: Synapse Date: 1999-02 Impact factor: 2.562
Authors: Stephan Urwyler; Mario F Pozza; Kurt Lingenhoehl; Johannes Mosbacher; Christina Lampert; Wolfgang Froestl; Manuel Koller; Klemens Kaupmann Journal: J Pharmacol Exp Ther Date: 2003-09-03 Impact factor: 4.030
Authors: Shinjae Chung; F Woodward Hopf; Hiroshi Nagasaki; Chun-Ying Li; James D Belluzzi; Antonello Bonci; Olivier Civelli Journal: Proc Natl Acad Sci U S A Date: 2009-04-02 Impact factor: 11.205