Benneyworth Michael A, Smith Randy L, Barrett Robert J, Sanders-Bush Elaine
Department of Pharmacology, Vanderbilt University School of Medicine, 8148 MRB III, Nashville, TN 37232, USA.
Psychopharmacology (Berl). 2005 Jun;179(4):854-62. doi: 10.1007/s00213-004-2108-z. Epub 2005 Jan 12.
The drug discrimination procedure is the most frequently used in vivo model of hallucinogen activity. Historically, most drug discrimination studies have been conducted in the rat. With the development of genetically modified mice, a powerful new tool has become available for investigating the mechanisms of drug-induced behavior. The current paper is part of an ongoing effort to determine the utility of the drug discrimination technique for evaluating hallucinogenic drugs in mice.
To establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice.
Using a two-lever drug discrimination procedure, C57Bl/6J mice were trained to discriminate 0.45 mg/kg LSD vs saline on a VI30 sec schedule of reinforcement, with vanilla-flavored Ensure serving as the reinforcer.
As in rats, acquisition was orderly, but the training dose was nearly five-fold higher for mice than rats. LSD lever selection was dose-dependent. Time-course studies revealed a rapid loss of the LSD stimulus effects. The 5-HT(2A/2C) receptor agonist, 2,5-dimethoxy-4-bromoamphetamine [(-)DOB] (1.0 mg/kg), substituted fully for LSD and the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) (1.6 mg/kg), substituted partially for LSD. Pretreatment with the 5-HT(2A) receptor-selective antagonist, MDL 100907, or the 5-HT(1A)-selective antagonist WAY 100635, showed that each antagonist only partially blocked LSD discrimination. Substitution of 1.0 mg/kg (-)DOB for LSD was fully blocked by pretreatment with MDL 100907 but unaltered by WAY 100635 pretreatment.
These data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.
药物辨别程序是致幻剂活性研究中最常用的体内模型。从历史上看，大多数药物辨别研究都是在大鼠身上进行的。随着基因工程小鼠的发展，一种强大的新工具可用于研究药物诱导行为的机制。本文是确定药物辨别技术在评估小鼠致幻药物方面效用的持续努力的一部分。
建立训练程序并描述小鼠中（+）麦角酸二乙酰胺（LSD）的刺激特性。
使用双杠杆药物辨别程序，以香草味Ensure作为强化物，对C57Bl/6J小鼠进行训练，使其在每30秒一次强化的可变间隔（VI）时间表上区分0.45mg/kg的LSD和生理盐水。
与大鼠一样，习得过程是有序的，但小鼠的训练剂量几乎是大鼠的五倍。LSD对杠杆的选择具有剂量依赖性。时程研究显示LSD的刺激作用迅速消失。5-羟色胺（5-HT）（2A/2C）受体激动剂2,5-二甲氧基-4-溴苯丙胺[（-）DOB]（1.0mg/kg）可完全替代LSD，而5-HT（1A）受体激动剂8-羟基-2-（二正丙基氨基）四氢化萘（8-OH-DPAT）（1.6mg/kg）可部分替代LSD。用5-HT（2A）受体选择性拮抗剂MDL 100907或5-HT（1A）选择性拮抗剂WAY 100635进行预处理表明，每种拮抗剂仅部分阻断LSD辨别。用MDL 100907预处理可完全阻断用1.0mg/kg（-）DOB替代LSD，但WAY 100635预处理则无此作用。
这些数据表明，在小鼠中，LSD的刺激作用既有5-HT（2A）受体成分，也有5-HT（1A）受体成分。
