Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice.
C M Krall, J B Richards, R A Rabin, Jerrold C Winter
Pharmacology, Biochemistry, and Behavior January 2008 DOI: 10.1016/j.pbb.2007.09.006 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study Peer reviewed |
|---|---|
| Population | SERT knockout mice and wildtype littermates |
| Interventions | LSD Pentobarbital |
| Dose | LSD 0.17 or 0.30 mg/kg; pentobarbital 15 or 30 mg/kg |
| Topics | LSD Serotonin |
| Key findings | LSD established stimulus control in 90% of wildtype mice but only 31% of SERT knockout mice, while pentobarbital did so in 80% of wildtype and 54% of knockout mice, suggesting reduced 5-HT1A and/or 5-HT2A receptor density underlies LSD's diminished efficacy. |
Abstract
Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT2A receptors, with serotonergic receptors of the 5-HT1A and 5-HT2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT2A receptor density is decreased and, at a functional level, the head-twitch response following the administration of DOI, an index of activation of 5-HT2A 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. Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice. 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. 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. 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-HT1A and/or 5-HT2A receptors underlies the absence of stimulus control by LSD.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 12
- Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms Pharmacological Reviews December 16, 2020
- d-Lysergic Acid Diethylamide (LSD) as a Model of Psychosis: Mechanism of Action and Pharmacology International Journal of Molecular Sciences November 23, 2016
- The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen Psychopharmacology February 19, 2010
- DARK Classics in Chemical Neuroscience: NBOMes ACS Chemical Neuroscience October 28, 2019
- Salvinorin A fails to substitute for the discriminative stimulus effects of LSD or ketamine in Sprague-Dawley rats. Pharmacology, Biochemistry, and Behavior September 1, 2010
and 7 more in the library
Cites 13
- Transcriptome Fingerprints Distinguish Hallucinogenic and Nonhallucinogenic 5-Hydroxytryptamine 2A Receptor Agonist Effects in Mouse Somatosensory Cortex Journal of Neuroscience October 1, 2003
- Neuropharmacological reassessment of the discriminative stimulus properties ofd-lysergic acid diethylamide (LSD) Psychopharmacology 1987
- The paradox of 5-methoxy-N,N-dimethyltryptamine: an indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors. Pharmacology, Biochemistry, and Behavior 2000
- Mescaline and lysergic acid diethylamide (LSD) as discriminative stimuli Psychopharmacology 1971
- Complex discriminative stimulus properties of (+)lysergic acid diethylamide (LSD) in C57Bl/6J mice Psychopharmacology January 11, 2005
and 8 more in the library