GABAB Receptors and Alcohol Use Disorders: Preclinical Studies.
GABAB Receptors and Alcohol Use Disorders: Preclinical Studies.
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DOI：
10.1007/7854_2020_178
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发表时间：
2022-01-01
影响因子：
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通讯作者：
Weerts, Elise M
中科院分区：
文献类型：
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作者：
Holtyn, August F;Weerts, Elise M
过去几十年的临床前研究已经证明了γ-氨基丁酸B（GABAB）受体在酒精使用障碍（AUD）中的作用。本章提供了一个检查的临床前证据的作用，GABAB受体对酒精相关的行为与GABAB受体激动剂巴氯芬，其影响已被最广泛的研究，和积极的变构调节剂（PAM）的GABAB受体。采用啮齿动物和非人灵长类动物模型的研究表明，GABAB受体的激活可以减少（1）酒精的刺激和奖赏作用;（2）身体依赖酒精的大鼠的酒精戒断症状;（3）在两瓶酒精对水选择程序下获得和维持饮酒;（4）在口服操作性自我给药程序下的酒精摄入;（5）使用消光和累进比率程序测量的酒精的动机特性;（6）戒酒一段时间后酒精摄入量的增加（酒精剥夺效应或ADE）;以及（7）当酒精不再可用时，酒精暗示和压力恢复酒精寻求的能力。巴氯芬和GABAB PAM在不同的临床前模型中减少了上述行为，这为GABAB受体在酒精相关行为中的重要作用提供了强有力的证据，并支持开发靶向GABAB受体的药物用于治疗AUD。本章强调了在多个动物模型中检查酒精相关行为机制的价值，以增加识别新治疗靶点的信心。
Preclinical research over the past several decades has demonstrated a role for the gamma-aminobutyric acidB (GABAB) receptor in alcohol use disorder (AUD). This chapter offers an examination of preclinical evidence on the role of the GABAB receptor on alcohol-related behaviors with a particular focus on the GABAB receptor agonist baclofen, for which effects have been most extensively studied, and positive allosteric modulators (PAMs) of the GABAB receptor. Studies employing rodent and non-human primate models have shown that activation of the GABAB receptor can reduce (1) stimulating and rewarding effects of alcohol; (2) signs of alcohol withdrawal in rats made physically dependent on alcohol; (3) acquisition and maintenance of alcohol drinking under a two-bottle alcohol versus water choice procedure; (4) alcohol intake under oral operant self-administration procedures; (5) motivational properties of alcohol measured using extinction and progressive ratio procedures; (6) the increase in alcohol intake after a period of alcohol abstinence (the alcohol deprivation effect or ADE); and (7) the ability of alcohol cues and stress to reinstate alcohol seeking when alcohol is no longer available. Baclofen and GABAB PAMs reduce the abovementioned behaviors across different preclinical models, which provides strong evidence for a significant role of the GABAB receptor in alcohol-related behaviors and supports development of medications targeting GABAB receptors for the treatment of AUD. This chapter highlights the value of examining mechanisms of alcohol-related behaviors across multiple animal models to increase the confidence in identification of new therapeutic targets.