Methamphetamine and Parkinson's disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles.

Figure 1

Time-course of TH and DAT fiber lost change after methamphetamine administration. Photomicrographs of striatal sections from mice treated with saline or METH stained for TH and DAT to illustrate the loss (1 day) and the partial recovery (7 days) of dopamine fibers that occur after methamphetamine administration. Animals were killed 1 and 7 days after treatment. Bar indicates 500 μm.

Figure 2

TH- and DAT-ir loss is predominant in striosomes. Serially adjacent sections from a mouse treated with METH stained for TH (A), MOR-1 (B), and DAT (C). Most striatal TH weak patches matched DAT weak patches. These areas corresponded with striosomes as demonstrated by MOR-1 immunostaining. A′–C′ show an example of a striosome at higher magnification. Bar indicates 500 μm (A–C) and 200 μm, (A–C′). Modified from Granado et al. [6].

Figure 3

Methamphetamine and MDMA increase the expression of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS) in mouse striatum. Photomicrographs of striatal sections of mice treated with saline or methamphetamine (5 mg/kg × 3) or MDMA (20 mg/kg × 3) stained for iNOS and nNOS. Animals were killed 1 day after treatment. Bar indicates 10 μm for iNOS and 50 μm for nNOS. Modified from Granado et al. [13].

Figure 4

Metamphetamine produces microglial activation in mouse striatum (Str) but not in nucleus accumbens (NAc). Photomicrographs of sections of Str and NAcc of mice treated with saline or metahmphetamine (5 mg/kg × 3) stained for Mac-1. Animals were killed 1 day after methamphetamine treatment for Mac-1. Bar indicates 100 μm.

Figure 5

Reduced DAT function in methamphetamine users. PET images showing accumulation of (11C) WIN-35 428 in the striatum in a control subject, an abstinent methamphetamine subject, an abstinent methcathinone subject, and a PD patient 70–90 min after injection of (11C) WIN-35 428. Taken from McCann et al. [53].