Self‐administration of methamphetamine alters gut biomarkers of toxicity

Abstract

Methamphetamine (METH) is a highly abused psychostimulant that is associated with an increased risk for developing Parkinson’s disease (PD). This enhanced vulnerability likely relates to the toxic effects of METH that overlap with PD pathology, for example, aberrant functioning of α-synuclein and parkin. In PD, peripheral factors are thought to contribute to central nervous system (CNS) degeneration. For example, α-synuclein levels in the enteric nervous system (ENS) are elevated, and this precedes the onset of motor symptoms. It remains unclear whether neurons of the ENS, particularly catecholaminergic neurons, exhibit signs of METH-induced toxicity as seen in the CNS. The aim of this study was to determine whether self-administered METH altered the levels of α-synuclein, parkin, tyrosine hydroxylase (TH), and dopamine-β-hydroxylase (DβH) in the myenteric plexus of the distal colon ENS. Young adult male Sprague-Dawley rats self-administered METH for 3 h per day for 14 days and controls were saline-yoked. Distal colon tissue was collected at 1, 14, or 56 days after the last operant session. Levels of α-synuclein were increased, while levels of parkin, TH, and DβH were decreased in the myenteric plexus in the METH-exposed rats at 1 day following the last operant session and returned to the control levels after 14 or 56 days of forced abstinence. The changes were not confined to neurofilament-positive neurons. These results suggest that colon biomarkers may provide early indications of METH-induced neurotoxicity, particularly in young chronic METH users who may be more susceptible to progression to PD later in life.

Differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice

“…First, at least Meth can alter GI function in humans by causing intestinal ischemia [73] and infarction [74], and it can also lead to reductions in GI motility and paralytic ileus [75]. In animals, self-administration of Meth increases colon permeability [76] and gut toxicity [77]. Second, psychostimulants have long been used to suppress appetite as an aid to weight loss [78] and it is known that individuals with eating disorders have worsened symptoms and poorer outcomes if they co-abuse stimulants such as Meth [79].…”

SUMOylation of Alpha-Synuclein Influences on Alpha-Synuclein Aggregation Induced by Methamphetamine

“…Brain samples (prefrontal cortex and striatum tissues) were removed quickly, dissected on ice and stored at −80°C. We selected the prefrontal cortex and striatum because α-syn level was significantly increased in those two brain regions (Jiang et al, 2014 ; Wang and Witt, 2014 ; Flack et al, 2017 ). All animal procedures were performed according to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and were pre-approved in advance by the Institutional Animal Care and Use Committee at the Southern Medical University.…”

“…Furthermore, METH causes pathological changes similar to neurodegenerative diseases like Parkinson’s disease (PD; Garwood et al, 2006 ; Morrow et al, 2011 ). In both laboratory animals and humans, METH exposure increases the expression of alpha-synuclein (α-syn) in the striatum and prefrontal cortex (Jiang et al, 2014 ; Wang and Witt, 2014 ; Flack et al, 2017 ). α-Syn, a natively unfolded neuronal protein enriched in presynaptic terminals, has been involved in several neurodegenerative diseases, including PD and dementia with Lewy bodies (LBs).…”