The gamma-aminobutyric acid-B receptor agonist baclofen attenuates responding for ethanol in ethanol-dependent rats.
The gamma-aminobutyric acid-B receptor agonist baclofen attenuates responding for ethanol in ethanol-dependent rats.
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γ-氨基丁酸-B 受体激动剂巴氯芬可减弱乙醇依赖大鼠对乙醇的反应。
DOI：
10.1111/j.1530-0277.2006.00259.x
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Koob,GeorgeF
中科院分区：
文献类型：
--
作者：
Walker,BrendanM;Koob,GeorgeF
背景：γ-氨基丁酸-B(GABAB)受体激动剂已被证明能抑制非依赖大鼠操作性的乙醇自我给药。然而，很少有人关注GABA受体激动剂对依赖动物乙醇自身给药的影响。方法：在本实验中，本实验测试了GABA受体激动剂巴氯芬在非依赖和随后的酒精依赖诱导后对乙醇的固定(FR)和递增比率(PR)反应的调节能力。在获得和稳定基础可操作乙醇后，在诱导依赖后，巴氯芬[0.0，0.5，1，2和4 mg/kg，腹腔注射(Ip)]检测FR-1对乙醇的反应。还评估了巴氯芬(2.0 mg/kg)在PR增援计划下影响反应的能力。结果：巴氯芬(0.0、0.5、1、2、4 mg/kg，剂量分别为0.0、0.5、1、2、4 mg/kg)在停药6小时后的操作室内恢复FR-1和PR巴氯芬药物试验(剂量如上)。Ip)剂量依赖地减少了非依赖和依赖大鼠在FR强化计划下的乙醇自身给药。然而，在乙醇蒸气暴露的动物中，显著降低对乙醇的反应的巴氯芬剂量向左移动，这表明长期接触乙醇的动物对巴氯芬的敏感性增加。当使用PR强化计划进行测试时，暴露在蒸汽中的动物的断点显著增加(即动物愿意在依赖状态下工作更多)。巴氯芬(2.0 mg/kg，ip)抑制非依赖和依赖动物的摄入量。结论：酒精依赖导致乙醇自我给药增加，这反映在乙醇摄入量增加和对强化的PR计划的反应增加。由于巴氯芬抑制乙醇自身给药，并显示依赖动物的药效增强，本实验表明GABA受体可能成为治疗慢性酒精中毒的潜在药物治疗靶点。
Background:γ‐Aminobutyric acid‐B (GABAB) receptor agonists have been shown to suppress operant self‐administration of ethanol in nondependent rats. However, little work has focused on the effects of GABABreceptor agonists on self‐administration of ethanol in dependent animals.Methods:In the present experiment, the GABABreceptor agonist baclofen was tested for the ability to modulate both fixed‐ (FR) and progressive‐ratio (PR) responding for ethanol in rats while nondependent and subsequently after ethanol dependence induction. Following the acquisition and stabilization of baseline operant ethanol self‐administration and after dependence induction, baclofen [0.0, 0.5, 1, 2, and 4 mg/kg, intraperitoneal (IP)] was tested on FR‐1 responding for ethanol. The ability of baclofen (2.0 mg/kg) to affect responding under a PR schedule of reinforcement was also evaluated. Dependence was induced in the animals by subjecting them to a 1‐month intermittent vapor‐exposure period in which animals were exposed to ethanol vapor for 14 h/d. Following the 1‐month period, the vapor‐exposed animals resumed FR‐1 and PR baclofen drug testing (doses as described above) in the operant chambers at a time point corresponding to the animals being 6 hours into withdrawal (i.e., 6 hours after the ethanol vapor had been discontinued for that day).Results:Baclofen (0.0, 0.5, 1, 2, and 4 mg/kg, IP) dose‐dependently decreased ethanol self‐administration in both nondependent and dependent rats on a FR schedule of reinforcement. However, the dose of baclofen that significantly reduced responding for ethanol was shifted to the left in the ethanol vapor‐exposed animals, indicating an increased sensitivity to baclofen in animals that were chronically exposed to ethanol. When tested using a PR schedule of reinforcement, there was a significant increase in the breakpoint for the vapor‐exposed animals (i.e., the animals were willing to work more in a dependent state). Baclofen (2.0 mg/kg, IP) suppressed intake for both nondependent and dependent animals.Conclusions:Ethanol dependence produced increased self‐administration of ethanol as reflected in increased ethanol intake and increased responding on a PR schedule of reinforcement. As baclofen suppressed ethanol self‐administration and showed evidence of increased potency in dependent animals, the present experiment suggests that the GABABreceptor could be a potential pharmacotherapeutic target for the treatment of chronic alcoholism.
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DOI：
10.1097/01.alc.0000071744.78580.78
发表时间：
2003
期刊：
Alcoholism, clinical and experimental research.
影响因子：
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作者：
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作者：
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DOI：
10.1111/j.1530-0277.1999.tb04272.x
发表时间：
1999-07-01
影响因子：
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作者：
Roberts, AJ;Heyser, CJ;Koob, GF
通讯作者：
Koob, GF
DOI：
--
发表时间：
1999-09
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
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作者：
Z. Xi;E. Stein
通讯作者：
Z. Xi;E. Stein