Smith Mark A, Yancey David L, Morgan Drake, Liu Yu, Froestl Wolfgang, Roberts David C S
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Psychopharmacology (Berl). 2004 Apr;173(1-2):105-11. doi: 10.1007/s00213-003-1706-5. Epub 2004 Jan 8.
Previous studies have strongly implicated a role for GABA(B) receptors in modulating the reinforcing effects of cocaine.
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.
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.
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.
These findings suggest that positive allosteric modulators of the GABA(B) receptor may hold promise as potential pharmacotherapies for cocaine abuse and dependence.
先前的研究强烈表明γ-氨基丁酸B（GABA(B)）受体在调节可卡因的强化作用中发挥作用。
本研究的目的是检验两种新型GABA(B)受体正向变构调节剂CGP7930和GS39783在不同强化程序下降低大鼠可卡因自我给药的效果。
训练大鼠在累进比率（PR）、固定比率（FR）和离散试验（DT）强化程序下自我给药可卡因，并检验CGP7930和GS39783降低可卡因维持反应的能力。
在PR程序中，CGP7930以剂量依赖的方式显著降低每注射1.5毫克/千克可卡因维持的断点。GS39783仅使可卡因强化的断点适度降低，只有最高剂量相对于基线降低了断点。在FR1强化程序中，两种药物均降低了阈剂量可卡因的反应，但未改变更高剂量可卡因的反应。在DT程序中，每注射1.5毫克/千克可卡因在24小时实验期间每小时的三次10分钟试验中提供（DT3），产生了一种昼夜反应模式，其特征是在黑暗期输注次数多，在光照期输注次数少。在周期黑暗期开始时给予30毫克/千克CGP7930、3.0毫克/千克GS39783和2.5毫克/千克巴氯芬的剂量显著降低了可卡因维持的反应。在所有程序中，CGP7930在降低可卡因自我给药方面比GS39783更有效，这一发现可能是由于两种药物生物利用度的差异。
这些发现表明，GABA(B)受体正向变构调节剂有望成为可卡因滥用和依赖的潜在药物治疗方法。
