title: N-phenylpropyl-N'-substituted piperazines occupy sigma receptors and alter methamphetamine-induced hyperactivity in mice.
abstract: This study examined the effect of the N-phenylpropyl-N'-substituted piperazine ligands SA4503 (3.4-dimethoxyphenethyl), YZ-067 (4-methoxyphenethyl), YZ-185 (3-methoxyphenethyl) and Nahas-3h (4-methoxybenzyl) on methamphetamine-induced hyperactivity in mice. In a previous study in rats, SA4503 increased methamphetamine-induced hyperactivity at a lower ligand dose and enhanced it at a higher dose. The other ligands have not been investigated in this assay. Presently, mice were administered sigma ligands, and specific [125I]E-IA-DM-PE-PIPZE and [125I]RTI-121 binding was measured to determine σ1 sigma receptor and dopamine transporter occupancy, respectively. Mice were also administered sigma ligands followed by methamphetamine, and locomotor activity was measured. Each of the ligands occupied σ1 sigma receptors (ED50=0.2-0.6μmol/kg) with similar potency, but none occupied the transporter (ED50>10μmol/kg). At the highest dose tested (31.6μmol/kg) all four sigma ligands significantly attenuated methamphetamine-induced hyperactivity. Interestingly, SA4503, YZ-067 and Nahas-3h, but not YZ-185, enhanced methamphetamine-induced hyperactivity at lower ligand doses (1-3.16μmol/kg). These results suggest that these ligands function as stimulant agonists at lower doses and as antagonists at higher does, with subtle changes in the substitution pattern at the 3- and 4-positions of the phenethyl group contributing to the nature of the interactions. Overall, these data indicate a complex role for σ1 sigma receptor ligands in methamphetamine's behavioral effects.
authors.affiliation: Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, USA; Center for Translational Neuroscience, College of Medicine, University of Missouri, Columbia, MO 65211, USA. Electronic address: millerden@missouri.edu.
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Miller
authors.affiliation: Center for Translational Neuroscience, College of Medicine, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Park
authors.affiliation: Department of Chemistry, University of Missouri, Columbia, MO 65211, USA; Research Reactor Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Susan Z
authors.initials: SZ
authors.lastname: Lever
authors.affiliation: Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA; Department of Radiology, University of Missouri, Columbia, MO 65211, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Lever
mesh_terms: D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D006948:Hyperkinesis / Q000139:chemically induced*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D017480:Receptors, sigma / Q000819:agonists / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship
chemical_list: D010879:Piperazines; D017480:Receptors, sigma; C079213:RTI 121; D008694:Methamphetamine; C101789:SA 4503; D003042:Cocaine
keywords: Behavior; Dopamine transporter; Locomotor activity; Methamphetamine; Mouse; Receptor occupancy; Sigma receptor