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J Psychopharmacol. 2019 Nov;33(11):1447-1455. doi: 10.1177/0269881119867603. Epub 2019 Aug 27.

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

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Behavioral Neuroscience and Drug Development, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.



Like other psychedelics, D-lysergic acid diethylamide (LSD) affects numerous serotonin receptors, and according to the current dogma, the 5-HT2A receptors are considered the main target for its hallucinogenic effects. LSD, however, also displays agonistic activity at the 5-HT5A receptors, which mediate some of LSD-induced behavioural effects.


Using male Sprague Dawley rats, we examined the effects of 5-HT2A and 5-HT5A receptor antagonists on LSD-induced stimulus control in the two-lever drug discrimination test using a FR10 schedule of reinforcement.


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-HT5A 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.


The present results suggest that antagonists of the 5-HT5A receptor may inhibit subjective effects of LSD in rats.


5-HT2A receptor; 5-HT5A receptor; LSD; drug discrimination; psychedelic; serotonin


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