Lobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 immunoreactivity and monoamine depletions in the striatum

Abstract

ABSTRACT L-Lobeline is an alkaloid that inhibits the behavioral effects of methamphetamine (METH) in rats. No studies have examined the effects of lobeline on the acute and long-term neurochemical changes produced by neurotoxic doses of METH. The effects of lobeline on METH-induced dopamine release, alterations in vesicular monoamine transporter 2 (VMAT-2) distribution, and long-term depletions of dopamine and serotonin (5-HT) content in the rat striatum were examined. METH increased body temperature and dopamine release, decreased VMAT-2 immunoreactivity at 1 and 24 h after METH, and decreased dopamine and 5-hydroxytryptamine (5-HT) content in striatum when examined 7 days later. Prevention of METH-induced hyperthermia attenuated the decrease in VMAT-2 as well as dopamine and 5-HT content. Lobeline pretreatment did not affect METH-induced dopamine release but attenuated the decreases in VMAT-2 after METH and the long-term decreases in striatal dopamine and 5-HT content. These effects of lobeline were due partly to the attenuation of METH-induced hyperthermia. The maintenance of hyperthermia during lobeline ϩ METH exposure restored the effects of METH on decreases in VMAT-2 as well as dopamine and 5-HT content. To examine the effects of lobeline independent of its effects on METHinduced hyperthermia, lobeline was administered after METH when body temperature returned to normal. Lobeline treatment at 5 and 7 h after METH attenuated the METH-induced decreases in synaptosomal, membrane-associated, and vesicular VMAT-2 24 h after METH, as well as the METH-induced decreases in dopamine and 5-HT content 7 days later. Therefore, lobeline has both temperature-dependent and -independent neuroprotective effects against METH toxicity. Methamphetamine (METH, ice, crystal) is an amphetamine derivative whose use has increased exponentially in the United States. METH is a significant health concern because of its abuse liability and potential neurotoxic effects, which include long-term monoamine depletions, degradation of both dopamine and serotonin (5-HT) striatal terminals in rodents and primates METH also affects the vesicular monoamine transporter 2 (VMAT-2), the protein that regulates the sequestration of monoamines into vesicles for subsequent release. Repeated administrations of high doses of METH cause a loss of VMAT protein on the vesicular membrane 1 h after a repeated high-dose regimen of METH It has been hypothesized that METH disrupts the vesicular sequestration of dopamine, leading to the accumulation of dopamine and, consequently, the production of dopaminederived reactive oxygen species and quinones within the cytosol of the dopamine termina