Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Rationale: Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT_2A receptors, with serotonergic receptors of the 5-HT_1A and 5-HT_2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT_2A receptor density is decreased and, at a functional level, the head-twitch response following the administration of DOI, an index of activation of 5-HT_2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter. Objective: Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice. Methods: SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle. Results: The visual stimulus exerted control in both genotypes. LSD-induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital-induced stimulus control in 80% of WT mice and 54% of knockout mice. Conclusions: Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT_1A and/or 5-HT_2A receptors underlies the absence of stimulus control by LSD.