title: CM156, a high affinity sigma ligand, attenuates the stimulant and neurotoxic effects of methamphetamine in mice.
abstract: Methamphetamine (METH) is a highly addictive psychostimulant drug of abuse. Low and high dose administration of METH leads to locomotor stimulation, and dopaminergic and serotonergic neurotoxicity, respectively. The behavioral stimulant and neurotoxic effects of METH can contribute to addiction and other neuropsychiatric disorders, thus necessitating the identification of potential pharmacotherapeutics against these effects produced by METH. METH binds to σ receptors at physiologically relevant concentrations. Also, σ receptors are present on and can modulate dopaminergic and serotonergic neurons. Therefore, σ receptors provide a viable target for the development of pharmacotherapeutics against the adverse effects of METH. In the present study, CM156, a σ receptor ligand with high affinity and selectivity for σ receptors over 80 other non-σ binding sites, was evaluated against METH-induced stimulant, hyperthermic, and neurotoxic effects. Pretreatment of male, Swiss Webster mice with CM156 dose dependently attenuated the locomotor stimulation, hyperthermia, striatal dopamine and serotonin depletions, and striatal dopamine and serotonin transporter reductions produced by METH, without significant effects of CM156 on its own. These results demonstrate the ability of a highly selective σ ligand to mitigate the effects of METH.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Kaushal
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seminerio
authors.forename: Jamaluddin
authors.initials: J
authors.lastname: Shaikh
authors.forename: Mark A
authors.initials: MA
authors.lastname: Medina
authors.forename: Christophe
authors.initials: C
authors.lastname: Mesangeau
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Wilson
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.forename: Rae R
authors.initials: RR
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000633:toxicity*; D003042:Cocaine / Q000037:antagonists & inhibitors; D004298:Dopamine / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D005334:Fever / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D058990:Molecular Targeted Therapy; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012701:Serotonin / Q000032:analysis; D050486:Serotonin Plasma Membrane Transport Proteins / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D013457:Sulfur Compounds / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C549191:3-(4-(4-cyclohexylpiperazin-1-yl)butyl)benzo(d)thiazole-2(3H)-thione; D000697:Central Nervous System Stimulants; D010879:Piperazines; D020011:Protective Agents; D017480:Receptors, sigma; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D013457:Sulfur Compounds; D012701:Serotonin; D008694:Methamphetamine; D003042:Cocaine; D004298:Dopamine