Effects of positive allosteric modulators of the GABAB receptor on cocaine self-administration in rats

被引:74
作者
Smith, MA
Yancey, DL
Morgan, D
Liu, Y
Froestl, W
Roberts, DCS
机构
[1] Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA
[2] Novartis Pharma AG, Therapeut Area Nervous Syst, Basel, Switzerland
关键词
CGP7930; cocaine; discrete trials; GABA; GS39783; fixed ratio; progressive ratio; self-administration;
D O I
10.1007/s00213-003-1706-5
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:105 / 111
页数:7
相关论文
共 26 条
[1]   A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement [J].
Arnold, JM ;
Roberts, DCS .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1997, 57 (03) :441-447
[2]  
Ashby CR, 1999, SYNAPSE, V31, P151, DOI 10.1002/(SICI)1098-2396(199902)31:2<151::AID-SYN8>3.3.CO
[3]  
2-N
[4]  
Bischoff S, 1999, J COMP NEUROL, V412, P1
[5]   The GABAB agonist CGP 44532 decreases cocaine self-administration in rats:: demonstration using a progressive ratio and a discrete trials procedure [J].
Brebner, K ;
Froestl, W ;
Andrews, M ;
Phelan, R ;
Roberts, DCS .
NEUROPHARMACOLOGY, 1999, 38 (11) :1797-1804
[6]   Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules [J].
Brebner, K ;
Phelan, R ;
Roberts, DCS .
PSYCHOPHARMACOLOGY, 2000, 148 (03) :314-321
[7]   The GABAB antagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat [J].
Brebner, K ;
Froestl, W ;
Roberts, DCS .
PSYCHOPHARMACOLOGY, 2002, 160 (01) :49-55
[8]   Intra-VTA baclofen attenuates cocaine self-administration on a progressive ratio schedule of reinforcement [J].
Brebner, K ;
Phelan, R ;
Roberts, DCS .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2000, 66 (04) :857-862
[9]  
CAINE SB, 1994, J PHARMACOL EXP THER, V270, P209
[10]   Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats [J].
Campbell, UC ;
Lac, ST ;
Carroll, ME .
PSYCHOPHARMACOLOGY, 1999, 143 (02) :209-214