The 5-HT_1A receptor and the stimulus effects of LSD in the rat

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). Objective: 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: Twelve male Fischer 344 rats were trained in a two-lever, fixed-ratio (FR) 10, and food-reinforced task with LSD (0.1 mg/kg, i.p.; 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, s.c.; 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. Conclusion: 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.