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

Abstract

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.

Psychedelics

“…Increasing the LSD training dose to 0.30 mg/kg led to 1 of 10 of the remaining mice reaching criterion (total mice reaching criterion at both doses was only 31%). By contrast, Krall et al (2008) reported that 9 of 10 WT mice reached criterion at 0.30 mg/kg LSD. They note that when KO mice were trained to discriminate a visual stimulus, 85% of the mice exhibited operant behavior, whereas 100% of the WT mice reached criterion.…”

“…Based on the partial block of the LSD stimulus by M100907, the partial substitution of 8-OH-DPAT, and the partial blockade of the LSD stimulus by WAY-100635, the authors hypothesize that the LSD stimulus has a significant 5-HT 1A receptor component in mice, whereas the LSD stimulus appears to be solely mediated by 5-HT 2A receptor activation in rats. Krall et al (2008) investigated stimulus control by LSD in C57BL/6 mice that were homozygous for the SERT null mutation (SERT 2/2 ). They used a chamber with two snout-poke holes and an FR20 schedule of water reinforcement.…”

The serotonin 5-HT2A receptor agonist TCB-2: a behavioral and neurophysiological analysis

“…Further evidence that TCB-2 might have hallucinogenic effects in humans comes from previous data showing that TCB-2 substitutes for the hallucinogenic compounds LSD and DOI in LSD-and DOI-trained rats in a drug discrimination paradigm (McLean et al 2006). Additionally, as head twitches induced by both TCB-2 (current studies) and DOI (Basselin et al 2009;Qu et al 2005) are markedly reduced in SERT −/− mice compared to SERT +/+ mice, and as SERT −/− mice have a marked decrease in the ability to establish stimulus control to LSD in a drug discrimination task (90% in SERT +/+ mice versus 31% in SERT −/− mice; Krall et al 2008), together these findings might suggest that hallucinogenic effects of such serotonergic compounds, possibly including TCB-2, might be decreased in humans with lesser-expressing SERT polymorphisms (Hu et al 2006;Lesch et al 1996;Praschak-Rieder et al 2007;Wendland et al 2008). …”

d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology

“…Krall et al [118] investigated the LSD-induced stimulus control in Serotonin Transporter Knockout (SERT KO) mice. The efficacy of the stimulus control induced by LSD in these animals is markedly decreased.…”