CM156, a high affinity sigma ligand, attenuates the stimulant and neurotoxic effects of methamphetamine in mice

• Published in: Neuropharmacology Vol. 61; no. 5; pp. 992 - 1000
• Main Authors: Kaushal, Nidhi, Seminerio, Michael J., Shaikh, Jamaluddin, Medina, Mark A., Mesangeau, Christophe, Wilson, Lisa L., McCurdy, Christopher R., Matsumoto, Rae R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2011
• Subjects: Animals; Body Temperature - drug effects; Central Nervous System Stimulants - pharmacology; Central Nervous System Stimulants - toxicity; Cocaine - antagonists & inhibitors; Dopamine; Dopamine - analysis; Drug Evaluation, Preclinical; Fever - chemically induced; Fever - metabolism; Locomotor; Male; Methamphetamine; Methamphetamine - pharmacology; Methamphetamine - toxicity; Mice; Molecular Targeted Therapy; Motor Activity - drug effects; Motor Activity - physiology; Neurotoxicity; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - metabolism; Neurotoxicity Syndromes - pathology; Piperazines - pharmacology; Piperazines - therapeutic use; Protective Agents - pharmacology; Protective Agents - therapeutic use; Receptors, sigma - antagonists & inhibitors; Receptors, sigma - metabolism; Serotonin; Serotonin - analysis; Serotonin Plasma Membrane Transport Proteins - analysis; Serotonin Plasma Membrane Transport Proteins - drug effects; Serotonin Plasma Membrane Transport Proteins - metabolism; Sulfur Compounds - pharmacology; Sulfur Compounds - therapeutic use; σ Receptors; Dopamine; Serotonin; σ Receptors; Methamphetamine; METH; BD1063; ER; AC927; Neurotoxicity; SERT; ANOVA; DAT; ROS; MAM; NMDA; CM156; Locomotor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2011.06.028

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. ► CM156 attenuates methamphetamine (METH)-induced locomotor stimulation. ► CM156 attenuates METH-induced reductions in striatal dopamine and serotonin levels. ► CM156 attenuates METH-induced deficits in striatal DAT and SERT expression. ► CM156 attenuates METH-induced hyperthermia. ► CM156 (without METH) has no significant effects on the endpoints investigated.