Abstract
Methamphetamine is a highly addictive psychostimulant drug of abuse that causes neurotoxicity at high or repeated dosing. Earlier studies have demonstrated the ability of the selective sigma receptor ligand AC927 (N-phenethylpiperidine oxalate) to attenuate the neurotoxic effects of methamphetamine in vivo. However, the precise mechanisms through which AC927 conveys its protective effects remain to be determined. Using differentiated NG108-15 cells as a model system, the effects of methamphetamine on neurotoxic endpoints and mediators like apoptosis, necrosis, generation of reactive oxygen and nitrogen species (ROS/RNS) and dopamine release were examined in the absence and presence of AC927. Methamphetamine at physiologically relevant micromolar concentrations caused apoptosis in NG108-15 cells. At higher concentrations of methamphetamine, necrotic cell death was observed. At earlier time points, methamphetamine caused ROS/RNS generation which was detected by the fluorigenic substrate CMH2DCFDA in a concentration and time dependent manner. N-acetylcysteine, catalase, and L-NMMA inhibited the ROS/RNS fluorescence signal induced by methamphetamine, suggesting the formation of hydrogen peroxide and reactive nitrogen species. Exposure to methamphetamine also stimulated the release of dopamine from NG108-15 cells into the culture medium. AC927 attenuated methamphetamine-induced apoptosis, necrosis, ROS/RNS generation and dopamine release in NG108-15 cells. Together, the data suggest that modulation of sigma receptors can mitigate methamphetamine-induced cytotoxicity, ROS/RNS generation, and dopamine release in cultured cells.
- Received June 17, 2011.
- Revision received November 18, 2011.
- Accepted November 18, 2011.
- The American Society for Pharmacology and Experimental Therapeutics