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Neuropharmacology. 2015 Jun;93:146-54. doi: 10.1016/j.neuropharm.2015.01.013. Epub 2015 Jan 31.

Prior methamphetamine self-administration attenuates the dopaminergic deficits caused by a subsequent methamphetamine exposure.

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Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, United States.
School of Dentistry, University of Utah, Salt Lake City, UT 84112, United States.
School of Dentistry, University of Utah, Salt Lake City, UT 84112, United States. Electronic address:


Others and we have reported that prior methamphetamine (METH) exposure attenuates the persistent striatal dopaminergic deficits caused by a subsequent high-dose "binge" METH exposure. The current study investigated intermediate neurochemical changes that may contribute to, or serve to predict, this resistance. Rats self-administered METH or saline for 7 d. On the following day (specifically, 16 h after the conclusion of the final METH self-administration session), rats received a binge exposure of METH or saline (so as to assess the impact of prior METH self-administration), or were sacrificed without a subsequent METH exposure (i.e., to assess the status of the rats at what would have been the initiation of the binge METH treatment). Results revealed that METH self-administration per se decreased striatal dopamine (DA) transporter (DAT) function and DA content, as assessed 16 h after the last self-administration session. Exposure to a binge METH treatment beginning at this 16-h time point decreased DAT function and DA content as assessed 1 h after the binge METH exposure: this effect on DA content (but not DAT function) was attenuated if rats previously self-administered METH. In contrast, 24 h after the binge METH treatment prior METH self-administration: 1) attenuated deficits in DA content, DAT function and vesicular monoamine transporter-2 function; and 2) prevented increases in glial fibrillary acidic protein and DAT complex immunoreactivity. These data suggest that changes 24 h, but not 1 h, after binge METH exposure are predictive of tolerance against the persistence of neurotoxic changes following binge METH exposures.


Dopamine; Methamphetamine; Self-administration; Striatum; Tolerance

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