Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure

Lisa M. McFadden, Greg C. Hadlock, Scott C. Allen, Paula L. Vieira-Brock, Kristen A. Stout, Jonathan D. Ellis, Amanda J. Hoonakker, David M. Andrenyak, Shannon M. Nielsen, Diana G. Wilkins, Glen R. Hanson, Annette E. Fleckenstein

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37 Scopus citations

Abstract

Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a "binge" treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. Accordingly, the present study investigated the impact of METH self-administration on dopaminergic neuronal function. Results revealed that self-administration of METH, given according to a regimen that produces brain METH levels comparable with those reported postmortem in human METH abusers (0.06 mg/infusion; 8-h sessions for 7 days), decreased striatal dopamine transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 days after the last self-administration session. Increasing the METH dose per infusion did not exacerbate these deficits. These deficits were similar in magnitude to decreases in DAT densities reported in imaging studies of abstinent METH abusers. It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of binge-induced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers.

Original languageEnglish (US)
Pages (from-to)295-303
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume340
Issue number2
DOIs
StatePublished - Feb 1 2012

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

McFadden, L. M., Hadlock, G. C., Allen, S. C., Vieira-Brock, P. L., Stout, K. A., Ellis, J. D., Hoonakker, A. J., Andrenyak, D. M., Nielsen, S. M., Wilkins, D. G., Hanson, G. R., & Fleckenstein, A. E. (2012). Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure. Journal of Pharmacology and Experimental Therapeutics, 340(2), 295-303. https://doi.org/10.1124/jpet.111.188433