Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice

The drug discrimination procedure, a common method for studying hallucinogens, was extended to mice. Mice required a nearly five-fold higher dose of LSD than rats to learn the discrimination. The LSD stimulus effects were dose-dependent and short-lived. A 5-HT(2A/2C) receptor agonist fully substituted for LSD, while a 5-HT(1A) agonist partially substituted. Antagonists selective for 5-HT(2A) or 5-HT(1A) receptors each only partially blocked LSD discrimination, indicating that both receptor types contribute to LSD's effects in mice.

Study at a glance

Abstract

RationaleThe 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.ObjectiveTo establish the training procedures and characterize the stimulus properties of (+)lysergic acid diethylamide (LSD) in mice.MethodsUsing 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.ResultsAs 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.ConclusionsThese data suggest that in mice the stimulus effects of LSD have both a 5-HT(2A) receptor and a 5-HT(1A) receptor component.