Methamphetamine self-administration results in persistent dopaminergic pathology: implications for Parkinson's disease risk and reward-seeking.

Methamphetamine (Meth) abuse may be a risk factor for Parkinson's disease (PD); a problematic event as approximately 33 million people abuse Meth worldwide. The current study determined if a mild form of PD-like nigrostriatal pathology occurred following forced abstinence in Meth self-administering rats. The average daily intake of self-administered Meth was 3.6 ± 0.2 mg/kg/3 h over 14 sessions. Subsequently, animals were killed and the brains harvested at 1, 7, 28 or 56 days of abstinence. Post mortem, tyrosine hydroxylase (TH) immunostaining in the dorsal striatum progressively decreased throughout abstinence, reaching a 50% loss at 56 days. In the substantia nigra, there was marked reduction of TH+ cells, and Fluorogold (retrograde tracer) transport from the striatum to the nigra, at 28 and 56 days after Meth. Thus, Meth-induced progressive nigrostriatal damage occurred retrogradely, similar to PD pathology. The mesolimbic dopamine pathway [i.e. ventral tegmental area (VTA) and nucleus accumbens (NAc)], critical for Meth-induced reward, was also evaluated. TH immunostaining was decreased in the NAc-core at 28 and 56 days of forced abstinence, while staining in the dorsomedial NAc-shell was preserved. Accordingly, TH+ cell loss was evident in the lateral VTA, the origin of projections to the NAc-core, but not the medial VTA where NAc-shell projections originate. Thus, after Meth-taking ceased, a time-dependent, progressive degeneration occurred within nigrostriatal projections that eventually engulfed lateral mesolimbic projections. This pathological pattern is consistent with a trajectory for developing PD; therefore, these findings provide preclinical support for Meth abuse to increase vulnerability to developing PD.