Ginsburg B C, Lamb R J
Departments of Psychiatry and Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
Br J Pharmacol. 2014 Jul;171(14):3499-510. doi: 10.1111/bph.12707.
Drugs that more potently or effectively reduce ethanol-maintained behaviour versus an alternative are considered selective and are considered promising pharmacotherapies for alcoholism. Such results are often obtained using separate groups or multiple schedules where ethanol and the alternative are available alone or sequentially. Recently, we observed that when ethanol and food were available sequentially under a multiple schedule, fluvoxamine and varenicline were selective; yet this selectivity disappeared when ethanol and food were concurrently available.
We examined the generality of these findings by comparing doses of several drugs required to decrease ethanol- and food-maintained responding under a multiple schedule and under a concurrent schedule. Effects were determined for chlordiazepoxide, 2,5-dimethoxy-4-iodoamphetamine (DOI), meta-chlorophenylpiperazine (mCPP), morphine, naltrexone and d-amphetamine.
Under the multiple schedule, ED50 values for decreases in ethanol-maintained responding were significantly different and lower than ED50 s for decreases in food-maintained responding (demonstrating selectivity) for each drug except for chlordiazepoxide (which was equipotent) and naltrexone (which did not affect responding). However, this selectivity vanished or even inverted under the concurrent schedule, such that ED50 values for decreasing ethanol- and food-maintained responding were not different (or, following DOI, the ED50 for food-maintained responding was lower than for ethanol-maintained responding).
Results are consistent with those seen following fluvoxamine and varenicline administration, and suggest that selectivity is assay-dependent. These results indicate the need for careful interpretation of selective drug effects, especially when obtained in situations where ethanol or the alternative is the only programmed reinforcement available.
相较于其他替代物，能更有效或高效降低乙醇维持行为的药物被视为具有选择性，有望成为治疗酒精中毒的药物疗法。此类结果通常通过使用单独的组或多个实验安排来获得，在这些安排中，乙醇和替代物单独或依次可得。最近，我们观察到，当乙醇和食物在多重实验安排下依次可得时，氟伏沙明和伐尼克兰具有选择性；然而，当乙醇和食物同时可得时，这种选择性就消失了。
我们通过比较在多重实验安排和同时实验安排下降低乙醇维持反应和食物维持反应所需的几种药物剂量，来检验这些发现的普遍性。测定了氯氮卓、2,5-二甲氧基-4-碘苯丙胺（DOI）、间氯苯哌嗪（mCPP）、吗啡、纳曲酮和右旋苯丙胺的效果。
在多重实验安排下，除氯氮卓（等效）和纳曲酮（不影响反应）外，每种药物降低乙醇维持反应的半数有效剂量（ED50）值显著不同且低于降低食物维持反应的ED50值（表明具有选择性）。然而，在同时实验安排下，这种选择性消失甚至反转，以至于降低乙醇维持反应和食物维持反应的ED50值没有差异（或者，在DOI之后，食物维持反应的ED50低于乙醇维持反应的ED50）。
结果与给予氟伏沙明和伐尼克兰后的结果一致，表明选择性依赖于实验测定方法。这些结果表明，需要谨慎解释选择性药物效应，尤其是在乙醇或替代物是唯一设定强化物的情况下获得的结果。
