Mariathasan E.A., White J-A.W., Stolerman I.P.
Section of Behavioural Pharmacology, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK.
Behav Pharmacol. 1996 Aug;7(4):364-372. doi: 10.1097/00008877-199608000-00008.
The impact of training dose on the characteristics of a discrimination maintained by a mixture of two dissimilar drugs has been investigated in order to refine this approach to the study of drug interactions. Three groups of rats (n = 10) were trained to discriminate mixtures of (+)-amphetamine (0.2-0.8mg/kg) plus pentobarbitone (5-20mg/kg) from saline, in a two-lever operant procedure with food reinforcement, with the ratio of the doses held constant (amphetamine: pentobarbitone, 1:25). Discriminations were acquired to an accuracy of 90-97%. There was full generalisation to amphetamine alone, but only in rats trained with mixtures of the smaller doses of the single drugs. There was partial generalisation when either apomorphine (50%) or nicotine (63%) was administered alone, and the magnitude of these responses was inversely related to the dose of mixture used for training. Doses of pentobarbitone half of those used for training produced little discriminative response when administered alone to rats trained with the two smallest doses of the mixture; the same doses of pentobarbitone increased responses to amphetamine or apomorphine in a more than additive manner. Strikingly, some doses of apomorphine and pentobarbitone that did not generalise when administered separately, produced full generalisation when administered together, but only in rats trained with the smaller doses of the mixture. In contrast, pentobarbitone did not enhance generalisation to nicotine in any group. It was concluded that, on the one hand, patterns of generalisation to single drugs followed an orderly pattern resembling those for discriminations established with single drugs. On the other hand, there was a complex pattern of generalization from one mixture to another; thus, altering the doses of drugs used for training markedly influenced discriminations of an abused drug mixture, but no simple rules to predict the influence of training dose have been ascertained.
为了完善这种研究药物相互作用的方法，研究了训练剂量对由两种不同药物混合物维持的辨别特征的影响。三组大鼠（每组n = 10）在双杠杆操作性程序中接受训练，以食物强化，将（+）-苯丙胺（0.2 - 0.8mg/kg）加戊巴比妥（5 - 20mg/kg）的混合物与生理盐水区分开来，两种药物的剂量比例保持恒定（苯丙胺：戊巴比妥，1:25）。辨别准确率达到90 - 97%。对单独的苯丙胺有完全的泛化，但仅在使用较小剂量单一药物混合物训练的大鼠中出现。单独给予阿扑吗啡（50%）或尼古丁（63%）时出现部分泛化，这些反应的强度与用于训练的混合物剂量呈负相关。对用两种最小剂量混合物训练的大鼠单独给予戊巴比妥剂量减半时，产生的辨别反应很小；相同剂量的戊巴比妥以超过相加的方式增加了对苯丙胺或阿扑吗啡的反应。引人注目的是，一些单独给药时没有泛化的阿扑吗啡和戊巴比妥剂量，一起给药时产生了完全泛化，但仅在使用较小剂量混合物训练的大鼠中出现。相比之下，戊巴比妥在任何组中都没有增强对尼古丁的泛化。得出的结论是，一方面，对单一药物的泛化模式遵循一种有序模式，类似于用单一药物建立的辨别模式。另一方面，从一种混合物到另一种混合物存在复杂的泛化模式；因此，改变用于训练的药物剂量显著影响对滥用药物混合物的辨别，但尚未确定预测训练剂量影响的简单规则。
