Methamphetamine and mechanisms underlying tolerance to its neurotoxic effects.

Previous studies have demonstrated that pretreating with multiple injections of escalating doses of methamphetamine (METH) induces tolerance to the long-term neurotoxic effects of METH on dopamine (DA) neurons. The mechanism(s) underlying this tolerance phenomenon is (are) unknown. Recent studies suggested that aberrant vesicular monoamine transporter-2 (VMAT-2) and DA transporter function contribute to the neurotoxic effects of METH. Hence, the purpose of this study was to explore the role of the VMAT-2 and DA transporter in the induction of tolerance to the long-term persistent dopaminergic and serotonergic deficits caused by METH. A second purpose was to investigate the potential role of hyperthermia and alterations in brain METH distribution in this tolerance. Thus, we hypothesize that tolerance to the neurotoxic effects of METH is possibly due to either a shift in the drug distribution of METH in the brain and/or the prevention of METH-induced alterations in monoamine transporter function. Data from this dissertation revealed that the protection from METH pretreatment was not due to changes in the distribution of METH in the brain, as both the METH-pretreated and saline-pretreated rats had similar amounts of METH and amphetamine (AMP) in the brain after the last METH challenge injection. Depending on the dosing protocol employed, the METH pretreatment regimen could slightly attenuate METH-induced hyperthermia during the challenge administration, thus possibly contributing to the protection against long-term monoamine depletion. METH pretreatment regimen attenuated both the acute METH-induced decrease in VMAT-2 function 2 h after the METH challenge administration and its resulting persistent DA deficits in the striatum as well as serotonin (5-HT) deficits in the hippocampus. However, the pretreatment regimen did not produce tolerance by altering the acute METH-induced decrease in DA transporter uptake. Furthermore, pretreatment with METH prior to a high-dose METH challenge administration also attenuated the acute METH-induced redistribution of VMAT-2 immunoreactivity within the nerve terminal. In summary, these data are the first to demonstrate an association between the prevention of acute alterations in vesicular DA uptake and the development of tolerance to the neurotoxic effects of METH.