PT  - JOURNAL ARTICLE
AU  - Kamisha L. Johnson-Davis
AU  - Jannine G. Truong
AU  - Annette E. Fleckenstein
AU  - Diana G. Wilkins
TI  - Alterations in Vesicular Dopamine Uptake Contribute to Tolerance to the Neurotoxic Effects of Methamphetamine
AID  - 10.1124/jpet.103.062695
DP  - 2004 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 578--586
VI  - 309
IP  - 2
4099  - http://jpet.aspetjournals.org/content/309/2/578.short
4100  - http://jpet.aspetjournals.org/content/309/2/578.full
SO  - J Pharmacol Exp Ther2004 May 01; 309
AB  - Previous studies demonstrated that tolerance to the long-term neurotoxic effects of methamphetamine on dopamine neurons could be induced by pretreating with multiple injections of escalating doses of methamphetamine. The mechanism(s) underlying this tolerance phenomenon is unknown. Some recent studies suggested that aberrant vesicular monoamine transporter-2 (VMAT-2) and dopamine transporter function contribute to neurotoxic effects of methamphetamine. Hence, the purpose of this study was to explore the role of the VMAT-2 and dopamine transporter in the induction of tolerance to the longterm persistent dopaminergic deficits caused by methamphetamine. A second purpose was to investigate the potential role of hyperthermia and alterations in brain methamphetamine distribution in this tolerance. Results revealed that the methamphetamine pretreatment regimen attenuated both the acute methamphetamine-induced decrease in VMAT-2 function 2 h after the methamphetamine challenge administration and its resulting persistent dopamine deficits without attenuating the acute methamphetamine-induced decreases in dopamine transporter uptake. Furthermore, pretreatment with methamphetamine prior to a high-dose methamphetamine challenge administration also attenuated the acute methamphetamine-induced redistribution of VMAT-2 immunoreactivity within the nerve terminal. This protection was not due to alterations in concentration of methamphetamine in the brain because both the methamphetamine- and saline-pretreated rats had similar amounts of methamphetamine and amphetamine at 30 min to 2 h after the last methamphetamine challenge injection. In summary, these data are the first to demonstrate an association between the prevention of acute alterations in vesicular dopamine uptake and the development of tolerance to the neurotoxic effects of methamphetamine. The American Society for Pharmacology and Experimental Therapeutics