Attenuation of methamphetamine‐induced neurotoxicity by selective sigma receptor ligands: in vivo and in vitro studies

Abstract

Methamphetamine (METH) is one of the most widely abused illicit substances worldwide. It is capable of causing hyperthermia and neurotoxicity after high and/or repeated dosing. Selective ligands for sigma receptors were developed by our research team and shown in preclinical studies in male, Swiss Webster mice to significantly attenuate hyperthermia as well as several classical markers of METH neurotoxicity in the striatum: depletion of dopamine and 5‐HT levels, reductions in dopamine and 5‐HT transporter expression. Use of an NG108–15 cell culture model system to further delineate mechanisms underlying the protective effects of the sigma ligands reveals significant attenuation of METH‐induced ROS/RNS and caspase dependent pathways. In contrast, METH‐induced endoplasmic reticulum stress pathways are less affected by intervention with sigma ligands in NG108–15 cells. The relative contribution of each of the sigma receptor subtypes in the neuroprotective effects are still being elucidated, with preliminary data suggesting the importance of the sigma‐2 subtype. Together, the data indicate that sigma receptor ligands can intervene at numerous mechanisms that contribute to METH neurotoxicity. [Funding from NIDA: DA013978, DA023205]