THE SIGMA 1 RECEPTOR SELECTIVE LIGAND LS-1-1-137 ATTENUATES THE 2,5-DIMETHOXYIODOAMPHETAMINE - INDUCED HEAD TWITCH RESPONSE.

1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is known to cause hallucinations in humans and the administration of DOI in rodents has been reported to induce head twitches (Canal and Morgan 2012). DOI has been proposed as an animal model to identify drugs for the treatment of Tourette syndrome (TS) and other neuropsychiatric disorders. In this study, we used DOI-induced head twitch response (HTR) as our experimental model to screen antipsychotic properties of novel compounds. Our study results indicate that LS-1-137 may represent a novel antipsychotic drug. Purpose (a): 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) is known to cause hallucinations in humans and the administration of DOI in rodents has been reported to induce head twitches (Canal and Morgan 2012). DOI has been proposed as an animal model to identify drugs for the treatment of Tourette syndrome (TS) and other neuropsychiatric disorders. The exact mechanisms leading to head twitches in mice remain elusive. Several receptors, neural pathways and intracellular proteins have been implicated in the modulation of the HTR. However, no studies have investigated a possible role of sigma receptors in DOI-dependent HTR in mice. In this study we report the possible involvement of the sigma 1 receptor in the murine DOI dependent HTR in male DBA/2J mice and the ability of the novel sigma 1 vs. sigma 2 receptor selective compound, LS-1-137, to modulate that response. Methods (b): A filtration-binding assay was used to characterize the binding properties of novel sigma compound at D2 like dopamine, muscarinic, serotonin 2A and 2C and at sigma receptors. In this study, male DBA/2J mice were used. On the day of testing, mice were weighed and placed individually in an open ended Plexiglas cylinder with a clean paper towel floor, in a dimly lighted room. Animals were allowed to habituate to the cylinder for 15 minutes prior to the injection of vehicle (5% DMSO in sterile deionized water) or test drug intraperitoneal (i.p.). Five minutes later the DOI was administered to the animal by i.p. injection and the mouse was returned to the cylinder. A head twitch response was defined as a rapid left to right (or right to left) movement of the head, without the involvement of the limbs. Two observers counted the number of head twitches by visual examination and the number of head twitches was recorded at 5-minute intervals. The data points are presented as the mean values obtained by two observers. To evaluate the drug's effect on motor performance and coordination, a Rotarod test was performed. Results (c): LS-1-137 exhibits high affinity binding at sigma 1 receptors (Ki = 3.2 nM) and is 80-fold selective at sigma 1 versus sigma 2 receptors. It also binds with low affinity at D2-like (D2, D3 and D4) dopamine, muscarinic and serotonin (2A and 2C) receptors. In the present studies RHM-1-86, a sigma 2 receptor selective antagonist, was not able to attenuate the HTR. The sigma 1 receptor agonists PRE-084 and PPCC were also not able to inhibit the HTR. However, LS-1-137 and the sigma 1 antagonists haloperidol and BD1047 significantly inhibited the DOI-dependent HTR in DBA/2J mice. Furthermore, rotarod studies indicate that LS-1-137 does not compromise agility or muscular coordination in DBA/2J mice within a dose range capable of attenuating the effects of DOI. Conclusions (d): These observations implicate sigma 1 receptors in mediating the DOI-dependent HTR and suggest that LS-1-137 may have antipsychotic properties in vivo.