No abstract

2C-T-7 is effective in two rodent models of 5-HT2 agonist activity and has affinity at receptors relevant to hallucinogen effects. The effectiveness with which M100907 antagonizes the behavioral actions of 2C-T-7 strongly suggests that the 5-HT2A receptor is an important site of action for this compound.

These data, obtained using a stimulus control model of the hallucinogenic effects of PCP and LSD, provide support for the hypothesis that glutamate release is a factor in hallucinogenesis by both 5-HT(2) agonists and non-competitive NMDA antagonists.

Rationale-It has been suggested that the 5-HT 1A receptor plays a significant modulatory role in the stimulus effects of the indoleamine hallucinogen lysergic acid diethylamide (LSD).Objectives-The present study sought to characterize the effects of several compounds with known affinity for the 5-HT 1A receptor on the discriminative stimulus effects of LSD. Methods-12Male F-344 rats were trained in a two-lever, fixed ratio10, food reinforced task with LSD (0.1 mg/kg; IP; 15 min pretreatment) as a discriminative stimulus. Combination and substitution tests with the 5-HT 1A agonists, 8-OH-DPAT, buspirone, gepirone, and ipsapirone, with LSD-induced stimulus control were then performed. The effects of these 5-HT 1A ligands were also tested in the presence of the selective 5-HT 1A receptor antagonist, WAY-100,635 (0.3 mg/kg; SC; 30 min. pretreatment).Results-In combination tests stimulus control by LSD was increased by all 5-HT 1A receptor ligands with agonist properties. Similarly, in tests of antagonism, the increase in drug-appropriate responding caused by stimulation of the 5-HT 1A receptor was abolished by administration of WAY-100,635.Conclusions-These data, obtained using a drug discrimination model of the hallucinogenic effects of LSD, provide support for the hypothesis that the 5-HT 1A receptor has a significant modulatory role in the stimulus effects of LSD.

Rationale-Drug-induced stimulus control has proven to be a powerful tool for the assessment of a wide range of psychoactive drugs. Though a variety of species have been employed, the majority of studies have been in the rat. However, with the development of techniques which permit the genetic modification of mice, the latter species has taken on new importance. Lysergic acid diethylamide [LSD], the prototypic indoleamine hallucinogen, has not previously been trained as a discriminative stimulus in mice.Objective-To demonstrate the feasibility of LSD-induced stimulus control in the mouse and to provide a preliminary characterization of the stimulus properties of LSD in that species.Methods-Male C57BL/6 mice were trained using a left or right nose-poke operant on a fixed-ratio 10, water reinforced task following the injection of lysergic acid diethylamide [LSD, 0.17 or 0.30 mg/kg, SC; 15 min pretreatment] or vehicle.Results-Stimulus control was established in 6 of 16 mice at a dose of LSD of 0.17 mg/kg after 39 sessions. An increase in dose to 0.30 mg/kg for the remaining mice resulted in stimulus control in an additional 5 subjects. In the low dose group, subsequent experiments demonstrated an orderly dose-effect relationship for LSD and a rapid offset of drug action with an absence of LSD effects 60 min after injection. When LSD [0.17 mg/kg] was administered in combination with the selective 5-HT 2A antagonist, M100907, LSD-appropriate responding was significantly but incompletely reduced to approximately 50%; concurrently, response rates declined significantly. In mice trained with a dose of LSD of 0.30 mg/kg, full generalization to the phenethylamine hallucinogen, [-]-2,5-dimethoxy-4-methylamphetamine [DOM] was observed.Conclusions-The present data demonstrate the feasibility of LSD-induced stimulus control in the mouse. The general features of stimulus control by LSD in the mouse closely resemble those observed in the rat but the present data suggest that there may be significant differences as well.