PT  - JOURNAL ARTICLE
AU  - Nidhi Kaushal
AU  - Meenal Elliott
AU  - Matthew J Robson
AU  - Anand Krishnan V Iyer
AU  - Yon Rojanasakul
AU  - Andrew Coop
AU  - Rae R Matsumoto
TI  - AC927, a sigma ligand, blocks methamphetamine-induced release of dopamine and generation of reactive oxygen species in NG108-15 cells
AID  - 10.1124/mol.111.074120
DP  - 2011 Nov 18
TA  - Molecular Pharmacology
PG  - mol.111.074120
4099  - http://molpharm.aspetjournals.org/content/early/2011/11/18/mol.111.074120.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/11/18/mol.111.074120.full
AB  - 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.