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Rapid and reversible effects of methamphetamine on dopamine transporters
A E Fleckenstein1, R R Metzger, D G Wilkins
1Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Abstract:
Reactive oxygen species decrease dopamine transporter (DAT) function in vitro. Because of this, and the finding that METH administration causes oxygen radical formation in vivo, the effects of METH administration on DAT activity in rat striatum were investigated. A single METH injection caused a dose-dependent (0-15 mg/kg) decrease in [3H]dopamine uptake into striatal synaptosomes prepared 1 h after METH administration; an effect attributable to a decreased Vmax of [3H]dopamine uptake. Similarly, multiple high-dose administrations of METH (10 mg/kg/dose; four doses at 2-h intervals) decreased DAT function. The decreases in DAT activity after either single or multiple METH administrations were reversed 24 h after treatment. [3H]5HT transport into striatal synaptosomes was also affected by METH treatment. Taken together, these data suggest that METH decreases DAT activity, perhaps through a reactive oxygen species-mediated mechanism. These findings may have important implications regarding the role of oxidative events in the physiological regulation of monoaminergic systems.
Insights
Methamphetamine (METH) reduces dopamine transporter (DAT) function in rats, potentially via oxidative stress. DAT activity recovered within 24 hours after METH administration.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Reactive oxygen species (ROS) are known to impair dopamine transporter (DAT) function in vitro.
- Methamphetamine (METH) administration in vivo generates ROS, suggesting a potential link to DAT dysfunction.
Purpose of the Study:
- To investigate the effects of METH administration on DAT activity in the rat striatum.
- To explore the role of oxidative stress in METH-induced DAT alterations.
Main Methods:
- Rats were administered single or multiple doses of METH.
- DAT function was assessed by measuring [3H]dopamine uptake into striatal synaptosomes.
- Vmax of dopamine uptake was analyzed.
- [3H]5HT transport was also evaluated.
Main Results:
- Single METH injection caused a dose-dependent decrease in DAT activity, primarily affecting Vmax.
- Multiple high-dose METH administrations also reduced DAT function.
- DAT activity returned to baseline levels 24 hours post-METH treatment.
- METH also impacted [3H]5HT transport.
Conclusions:
- METH administration decreases DAT activity in the rat striatum.
- This effect may be mediated by reactive oxygen species.
- The findings suggest oxidative events play a role in regulating monoaminergic systems.