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Development of Partial Tolerance to the Suppressing Effect of the Positive Allosteric Modulator of the GABAB Receptor, KK-92A, on Alcohol Self-Administration in Rats.
Alcohol and Alcoholism ( IF 2.8 ) Pub Date : 2022-11-11 , DOI: 10.1093/alcalc/agac026
Paola Maccioni 1 , Katarzyna Kaczanowska 2 , Patricia McDonald 3 , Giancarlo Colombo 1
Affiliation  

AIMS A recent study reported how acute treatment with KK-92A, a newly synthesized positive allosteric modulator (PAMs) of the GABAB receptor (GABAB PAMs), suppressed a series of alcohol-related behaviors, including operant oral alcohol self-administration, in selectively bred Sardinian alcohol-preferring (sP) rats. These findings lead to the addition of KK-92A to the long list of GABAB PAMs capable of reducing, after acute treatment, alcohol self-administration in rats. As a further step toward a more complete characterization of the anti-addictive properties of KK-92A, the present study was designed to assess the effect of repeated treatment with the compound on alcohol self-administration. METHODS sP rats were trained to lever-respond for oral alcohol (15%, v/v) under the fixed ratio 5 (FR5) schedule of reinforcement. Once lever-responding behavior had stabilized, KK-92A (0, 5, 10 and 20 mg/kg, i.p.) was administered 30 min prior to 10 consecutive daily self-administration sessions (likewise occurring under the FR5 schedule). RESULTS The first injection of KK-92A produced a dose-related suppression in number of lever-responses for alcohol and amount of self-administered alcohol. Magnitude of the suppressing effect of KK-92A decreased over the following two self-administration sessions and then tended to stabilize on continuation of treatment. Statistical significance at post hoc analysis was maintained only by the highest dose tested (20 mg/kg). CONCLUSIONS These data suggest the development of partial tolerance to the reducing effect of repeatedly administered KK-92A on alcohol self-administration. The agonistic component of the ago-allosteric profile of KK-92A is discussed as the likely key element underlying the observed tolerance.

中文翻译:

对大鼠酒精自我给药的 GABAB 受体正变构调节剂 KK-92A 的抑制作用的部分耐受性的发展。

目的 最近的一项研究报告了 KK-92A(一种新合成的 GABAB 受体正变构调节剂 (PAM))急性治疗如何选择性地抑制一系列酒精相关行为,包括操作性口服酒精自我给药饲养撒丁岛嗜酒 (sP) 大鼠。这些发现导致将 KK-92A 添加到长长的 GABAB PAM 列表中,该列表能够在急性治疗后减少大鼠的酒精自我给药。为了更全面地表征 KK-92A 的抗上瘾特性,本研究旨在评估重复使用该化合物治疗对酒精自我给药的影响。方法 训练 sP 大鼠在固定比率 5 (FR5) 强化计划下对口服酒精 (15%, v/v) 做出杠杆反应。一旦杠杆反应行为稳定,KK-92A(0、5、10 和 20 mg/kg,ip)在连续 10 次每日自我给药前 30 分钟给药(同样发生在 FR5 时间表下)。结果 第一次注射 KK-92A 对酒精的杠杆反应数量和自我管理的酒精量产生了剂量相关的抑制。KK-92A 的抑制作用的幅度在接下来的两次自我给药期间下降,然后在继续治疗时趋于稳定。仅通过测试的最高剂量 (20 mg/kg) 维持事后分析的统计显着性。结论 这些数据表明对反复施用 KK-92A 对酒精自我施用的降低作用产生了部分耐受性。
更新日期:2022-05-20
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