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

Abstract

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.

Dopamine Receptors and the Persistent Neurovascular Dysregulation Induced by Methamphetamine Self-Administration in Rats

“…This dose is considerably lower than what is typically experimenter-administered to assess Meth-induced neurotoxicity, i.e., 9-40 mg/kg Meth wherein high-dose acute Meth treatment can result in severe losses (e.g., 60-70%) in striatal presynaptic DA markers within 1 day after treatment (see review by Yamamoto et al, 2010). In the same Meth self-administering rats used in the present study, we reported a progressive reduction in striatal tyrosine hydroxylase with a 50% reduction at 56 days following self-administration (Kousik et al, 2014), which is reminiscent of what is reported in human imaging studies, where Meth abusers abstinent from the drug for an average of 3 years only show a 20-30% loss in presynaptic striatal DA markers (McCann et al, 1998). Outcome differences between acute Meth treatment and self-administration may reflect differences in doses as well as the differences in the consequences of noncontingent versus contingent administration (i.e., selfadministration) (Jacobs et al, 2003;Palamarchouk et al, 2009;Reichel et al, 2012).…”

Prior nicotine self-administration attenuates subsequent dopaminergic deficits of methamphetamine in rats: role of nicotinic acetylcholine receptors

“…Although these diseases manifest with different clinical features, many of the disease processes at the cellular level appear to be similar (McCann et al, 1998; Sekine et al, 2001; Volkow et al, 2001; Volz et al, 2007; Vaughan and Foster, 2013; Zuo and Motherwell, 2013; Kousik et al, 2014). For instance, the primary pathology of Parkinson's disease is well documented and includes the loss of dopaminergic nerve terminal markers in the caudate/putamen (for review, see Granado et al, 2013).…”

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

“…Repeated METH administrations to humans (Sekine et al, 2001;Volkow et al, 2001;McCann et al, 2008) and rodents (McFadden et al, 2012;Kousik et al, 2014) cause long-term striatal dopaminergic deficits resembling some aspects of Parkinson's disease (PD) (McCann et al, 1998;Lotharius and Brundin, 2002;Kish et al, 2008). In fact, individuals with a history of amphetamine (AMPH)/METH abuse have an increased risk for developing PD (Callaghan et al, 2010(Callaghan et al, , 2012Curtin et al, 2015).…”

“…In fact, individuals with a history of amphetamine (AMPH)/METH abuse have an increased risk for developing PD (Callaghan et al, 2010(Callaghan et al, , 2012Curtin et al, 2015). Although the majority of patients with PD have never abused METH, overlapping neuropathologies may underlie the degenerative processes involving these two conditions (for review, see Granado et al, 2013;Kousik et al, 2014). Preclinical studies indicate that aberrant dopamine (DA) sequestration and release leading to oxidative stress might be one of the mechanisms that likely contribute to this dopaminergic damage (Fleckenstein et al, 1997;Lotharius and Brundin, 2002; for review, see Riddle et al, 2006).…”