Serotonin type 5A receptor antagonists inhibit D-lysergic acid diethylamide discriminatory cue in rats.

Abstract

<h4>Purpose</h4>Like other psychedelics, D-lysergic acid diethylamide (LSD) affects numerous serotonin receptors, and according to the current dogma, the 5-HT_2A receptors are considered the main target for its hallucinogenic effects. LSD, however, also displays agonistic activity at the 5-HT_5A receptors, which mediate some of LSD-induced behavioural effects.<h4>Methods</h4>Using male Sprague Dawley rats, we examined the effects of 5-HT_2A and 5-HT_5A receptor antagonists on LSD-induced stimulus control in the two-lever drug discrimination test using a FR10 schedule of reinforcement.<h4>Results</h4>In animals trained to discriminate 0.08 mg/kg LSD from vehicle 15 minutes after injection, LSD produced dose-related increases in response, with an ED50 (±95% confidence limits) of 0.0384 (± 0.025-0.051) mg/kg). LSD-like responses were observed when the training dose of LSD was given 5-30 but not 90 minutes before the test. Confirming earlier reports, the 5-HT antagonist ketanserin (2 mg/kg) attenuated the LSD response in 50% of rats, and due to pretreatment with 0.2 and 2 mg/kg MDL 100907, 63% and 67% of animals, respectively, failed to select the LSD lever. We then investigated the effects of two 5-HT_5A receptor antagonists, and we found that 56% and 60% of rats pretreated with 3 and 10 mg/kg SB 699551, respectively, failed to select the LSD lever. Due to pretreatment with 0.01 mg/kg ASP 5736, 58% of rats did not select the LSD lever. This dose also reduced the response rate but not the number of rats failing to complete the test.<h4>Conclusions</h4>The present results suggest that antagonists of the 5-HT_5A receptor may inhibit subjective effects of LSD in rats.

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