Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats.
BACKGROUND
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.
Smith
Mark A
MA
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Yancey
David L
DL
Morgan
Drake
D
Liu
Yu
Y
Froestl
Wolfgang
W
Roberts
David C S
DC
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000008:administration & dosage* / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018757:GABA Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D058786:GABA-B Receptor Agonists; D008297:Male; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology; D012055:Reinforcement Schedule; D012646:Self Administration
C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D003517:Cyclopentanes; D018757:GABA Modulators; D058786:GABA-B Receptor Agonists; C478058:N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine; D010636:Phenols; D011743:Pyrimidines; D018080:Receptors, GABA-B; D003042:Cocaine