Objective: To determine if Parkinson’s disease (PD)-like pathology occurs in brain and colon following termination of methamphetamine (meth) self-administration.

Background: Meth abuse increases the risk of developing PD by three-fold. Abstinent meth abusers exhibit neuroinflammation and nigrostriatal dysfunction. We revealed that rats self-administering meth exhibit progressive, withdrawal-time dependent reductions in tyrosine hydroxylase (TH); where like PD, striatal dysfunction precedes nigral dysfunction¹. The gastrointestinal system may be an early site for PD; e.g., α-synuclein (α-syn) is upregulated in the colon prior to clinical diagnosis. It is not known if meth abuse results in gut pathology.

Methods: Male Sprague-Dawley rats self-administered meth for 14 days; controls were saline-yoked. Forelimb akinesia was assessed every week. Brain and colon tissue was harvested one or 56 days after the last operant session and prepared for Western blotting or immunohistochemistry of α-syn and GFAP.

Results: Akinesia was not observed during, or one day after meth, but emerged after 56 days of abstinence (p=0.0001). One day after meth treatment, there were no changes in GFAP or α-syn in the striatum. Though previously no change in TH⁺ cell number was observed¹, the substantia nigra pars compacta (SN_pc) exhibited a 50% increase in the number of α-syn⁺ cells (p=0.03). In the colon, meth self-administering rats showed a 24% increase in GFAP (p=0.0003) and 69% increase in α-syn (p=0.0001) immunoreactivity². Following 56 days of meth abstinence, when we previously observed a 22% decrease in SN_pc TH⁺ cells¹, the number of α-syn⁺ cells was still enhanced by 43% (p=0.005). Colonic GFAP and α-syn returned to control levels.

Conclusions: These data dovetail with our prior work to show that meth initiates subclinical nigrostriatal and colonic PD-like dysregulation, which, upon protracted abstinence, progresses to nigrostrial dysfunction that is associated with akinesia, even though the colon recovers. These studies offer insights into the enhanced vulnerability of meth abusers to develop PD.

 * These authors contributed equally.

References: ¹Kousik,S.M., Carvey,P.M., Napier,T.C., 2014. Methamphetamine self-administration results in persistent dopaminergic pathology: implications for Parkinson’s disease risk and reward-seeking. Eur. J. Neurosci., 40, 2707-2714

²Napier, T.C., Kousik, S.M., Kelly, L.P., Graves, S.M., Persons, A.L. Rats that self-administer methamphetamine show Parkinson’s Disease-like inflammation and α-synuclein pathology in the brain and colon. Presented at: Society for Neuroscience; 2013; San Diego, CA. Abstract#240.12  

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsons-disease-like-pathology-in-the-rat-brain-and-colon-following-methamphetamine-self-administration/