The role of reactive oxygen species in methamphetamine self‐administration and dopamine release in the nucleus accumbens

Methamphetamine (METH) markedly increases dopamine (DA) release in the mesolimbic DA system, which plays an important role in mediating the reinforcing effects of METH. METH‐induced DA release results in the formation of reactive oxygen species (ROS), leading to oxidative damage. We have recently reported that ROS are implicated in behavior changes and DA release in the nucleus accumbens (NAc) following cocaine administration. The aim of this study was to evaluate the involvement of ROS in METH‐induced locomotor activity, self‐administration and enhancement of DA release in the NAc. Systemic administration of a non‐specific ROS scavenger, N‐tert‐butyl‐α‐phenylnitrone (PBN; 0, 50 and 75 mg/kg, IP) or a superoxide‐selective scavenger, 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl (TEMPOL; 0, 50 and 100 mg/kg, IP), attenuated METH‐induced locomotor activity without affecting generalized behavior in METH‐naïve rats. PBN and TEMPOL significantly attenuated METH self‐administration without affecting food intake. Increased oxidative stress was found in neurons, but not astrocytes, microglia or oligodendrocytes, in the NAc of METH self‐administering rats. In addition, TEMPOL significantly decreased METH enhancement of DA release in the NAc. Taken together, these results suggest that enhancement of ROS in the NAc contributes to the reinforcing effect of METH. In this study, we utilized physiological, neurochemical, molecular, immunohistochemical and behavioral methodologies to show that methamphetamine (METH) enhances the production of reactive oxygen species, which leads to enhanced dopamine release in the nucleus accumbens and METH self‐administration behavior. Drugs that reduce reactive oxygen species effectively reduced METH enhancement of dopamine release and subsequent self‐administration behavior.