Evaluation of the effects of alpha-phenyl-N-tert-butyl nitrone pretreatment on the neurobehavioral effects of methamphetamine

A relationship between formation of reactive oxygen species (ROS) and energ y depletion has been proposed to play an important role in mediating metham phetamine (METH)-induced neurotoxicity. To evaluate this relationship, we e xamined the effect of the spin-trap agent, alpha-phenyl-N-tert-butyl nitron e (PBN) on hyperthermia and self-injurious behavior (SIB) and striatal dopa mine (DA) depletion produced by METH (4 injections of 4 mg/kg, 2 hr interva ls, s.c.) in BALB/c mice. Repeated administration of METH induced hyperther mia, incidence of SIE and striatal DA depletion (84% after 3 days). Pretrea tment with PEN (4 injections of 60 or 120 mg/kg, i.p.) reduced METH-induced hyperthermia, but did not significantly attenuate METH-induced SIE or the striatal DA depletion. On the other hand, pretreatment with high doses of P EN (4 injections of 180 or 240 mg/kg, i.p.) protected against METH-induced hyperthermia and SIE, and PEN (180 mg/kg) also completely protected against the acute striatal DA depletion 60 min after the last injection of the dru g. However, the long-lasting striatal DA depletion was only attenuated by 5 2 or 56%, respectively. These results indicate that METH-induced hypertherm ia contributes to, but is not solely responsible fur METH-induced neurotoxi city, and supports a role for formation of ROS and other mechanisms in the generation of METH-induced striatal dopaminergic neurotoxicity. In addition , the difference in the efficacy of PEN to protect against the acute or lon g-lasting striatal DA depletion induced by METH may indicate that both ROS formation and other mechanisms are required for METH-induced neurotoxicity to develop. (C) 2000 Elsevier Science Inc. All rights reserved.