title: The effect of the sigma-1 receptor selective compound LS-1-137 on the DOI-induced head twitch response in mice.
abstract: Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.
authors.affiliation: University of North Texas Health Science Center, The Center for Neuroscience Discovery, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, United States.
authors.forename: Maninder
authors.initials: M
authors.lastname: Malik
authors.affiliation: University of North Texas Health Science Center, The Center for Neuroscience Discovery, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, United States.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rangel-Barajas
authors.affiliation: Radiochemistry Laboratory, Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, United States.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: University of North Texas Health Science Center, The Center for Neuroscience Discovery, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, United States. Electronic address: robert.luedtke@unthsc.edu.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D019416:Head Movements / Q000187:drug effects*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D000083:Acetanilides; D000662:Amphetamines; D009025:Morpholines; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C112868:N-(1-benzylpiperidin-4-yl)phenylacetamide; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine
keywords: 2,5-dimethoxy-4-iodoamphetamine (DOI); Antipsychotic activity; Head twitch response; Neuropsychiatric disorders; Sigma-1 receptors