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Methamphetamine decreases mouse striatal dopamine transporter activity: roles of hyperthermia and dopamine
V Sandoval1, G R Hanson, A E Fleckenstein
1Department of Pharmacology and Toxicology, 30 S. 200 E., Rm. 201, University of Utah, Salt Lake City, UT 84112, USA.
Abstract:
Multiple methamphetamine administrations rapidly decrease rat striatal dopamine transporter activity. To determine the species specificity of this phenomenon, the present studies examined effects of this stimulant on the dopamine transporter in mice. As in rats, multiple methamphetamine injections rapidly reduced striatal dopamine transporter activity; a decrease that was partially reversed 24 h later. Moreover, methamphetamine decreased binding of the dopamine transporter ligand, WIN35428, but to a lesser degree than the change in dopamine transporter function. These decreases did not appear to result from residual methamphetamine introduced by the original drug treatment. As in rats, hyperthermia contributed to this phenomenon. Unlike in rats, a role for dopamine was not observed in mice as dopamine depletion, resulting from alpha-methyl-p-tyrosine pretreatment, did not prevent this decrease. In addition, unlike in rats, pretreatment with either a dopamine D1 or D2 receptor antagonist (SCH23390 or eticlopride, respectively) did not attenuate the methamphetamine-induced reduction in dopamine uptake. These findings demonstrate both similarities and differences in the acute effects of methamphetamine on dopamine transporter function in mice and rats, and suggest the mouse as an additional model for assessing the acute effects of methamphetamine on the dopamine transporter.
Insights
Methamphetamine rapidly decreases dopamine transporter activity in mice, similar to rats, but with key differences. This study suggests mice are a viable model for investigating methamphetamine
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Methamphetamine (MA) is a potent psychostimulant with known neurotoxic effects.
- Previous studies in rats show MA rapidly decreases striatal dopamine transporter (DAT) activity.
- Species-specific responses to MA neurotoxicity warrant further investigation.
Purpose of the Study:
- To investigate the effects of MA on DAT activity and binding in mice.
- To compare the mechanisms underlying MA-induced DAT changes in mice versus rats.
- To evaluate the mouse as a model for MA neurotoxicity research.
Main Methods:
- Mice received multiple MA injections to assess striatal DAT activity and WIN35428 binding.
- Investigated the role of hyperthermia, dopamine depletion (using alpha-methyl-p-tyrosine), and receptor antagonism (D1 and D2) in MA's effects.
- Compared DAT function changes in pretreated versus non-pretreated mice.
Main Results:
- Multiple MA administrations rapidly reduced mouse striatal DAT activity, with partial reversal after 24 hours.
- MA decreased DAT ligand binding, but to a lesser extent than functional changes.
- Hyperthermia contributed to DAT reduction; unlike rats, dopamine depletion or D1/D2 receptor antagonism did not prevent MA-induced DAT decrease in mice.
Conclusions:
- Acute MA exposure affects DAT function and binding in mice similarly to rats, but with distinct underlying mechanisms.
- Dopamine depletion and D1/D2 receptor blockade do not protect against MA-induced DAT reduction in mice.
- Mice represent a suitable model for studying acute MA effects on DAT, complementing rat models.