JPET #188433 Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure

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) of their relevance to the study of METH abuse; and 2) the effects of non-contingent 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 selfadministration of METH, given according to a regimen that produces brain METH levels comparable to those reported post-mortem in human METH abusers (0.06 mg/infusion, 8-h sessions for 7 d), decreased striatal dopamine (DA) transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 d 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. Importantly, 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. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on October 27, 2011 as DOI: 10.1124/jpet.111.188433 at A PE T Jornals on A ril 1, 2017 jpet.asjournals.org D ow nladed from