The evaluation of AZ66, an optimized sigma receptor antagonist, against methamphetamine-induced dopaminergic neurotoxicity and memory impairment in mice

• Published in: The international journal of neuropsychopharmacology Vol. 16; no. 5; pp. 1033 - 1044
• Main Authors: Seminerio, Michael J., Hansen, Rolf, Kaushal, Nidhi, Zhang, Han-Ting, McCurdy, Christopher R., Matsumoto, Rae R.
• Format: Journal Article
• Language: English
• Published: Cambridge, UK Cambridge University Press 01.06.2013; Oxford University Press
• Subjects: Analysis of Variance; Animals; Avoidance Learning - drug effects; Benzothiazoles - therapeutic use; Body Temperature - drug effects; Disease Models, Animal; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine Uptake Inhibitors - toxicity; Male; Memory Disorders - drug therapy; Memory Disorders - etiology; Methamphetamine - toxicity; Mice; Neurotoxicity Syndromes - complications; Neurotoxicity Syndromes - etiology; Neurotransmitter Agents - pharmacokinetics; Piperazines - therapeutic use; Protein Binding - drug effects; Receptors, sigma - antagonists & inhibitors; Recognition (Psychology) - drug effects; Tritium - pharmacokinetics; Aopamine; memory; neurotoxicity; methamphetamine; σ receptors
• ISSN: 1461-1457; 1469-5111
• DOI: 10.1017/S1461145712000831

Sigma (σ) receptors have recently been identified as potential targets for the development of novel therapeutics aimed at mitigating the effects of methamphetamine. Particularly, σ receptors are believed to mitigate some of the neurotoxic effects of methamphetamine through modulation of dopamine, dopamine transporters and body temperature. Furthermore, recent evidence suggests that targeting σ receptors may prevent cognitive impairments produced by methamphetamine. In the present study, an optimized σ receptor antagonist, AZ66, was evaluated against methamphetamine-induced neurotoxicity and cognitive dysfunction. AZ66 was found to be highly selective for σ receptors compared to 64 other sites tested. Pretreatment of male, Swiss Webster mice with i.p. dosing of AZ66 significantly attenuated methamphetamine-induced striatal dopamine depletions, striatal dopamine transporter reductions and hyperthermia. Additionally, neurotoxic dosing with methamphetamine caused significant memory impairment in the object recognition test, which was attenuated when animals were pretreated with AZ66; similar trends were observed in the step-through passive avoidance test. Taken together, these results suggest that targeting σ receptors may provide neuroprotection against the neurotoxicity and cognitive impairments produced by methamphetamine.