Cerebrovascular Injury After Serial Exposure to Chronic Stress and Abstinence from Methamphetamine Self-Administration

Abstract

Cerebrovascular damage caused by either exposure to stress or the widely abused drug, methamphetamine (Meth) is known but stress and drug abuse frequently occur in tandem that may impact their individual cerebrovascular effects. This study examined their co-morbid cerebrovascular effects during abstinence from self-administered Meth after the exposure to chronic unpredictable stress (CUS). Exposure to CUS prior to unrestricted Meth self-administration had no effect on Meth intake in rats; however, the pro-inflammatory mediator cyclooxygenase-2 (COX-2) and the breakdown of cell-matrix adhesion protein β-dystroglycan in isolated cerebral cortical capillaries were increased after 3 days of abstinence and persisted for 7 days. These changes preceded decreases in occludin, a key structural protein component of the blood-brain barrier. The decrease in occludin was blocked by the COX-2 specific inhibitor nimesulide treatment during abstinence from Meth. The changes in COX-2, β-dystroglycan, and occludin were only evident following the serial exposure to stress and Meth but not after either one alone. These results suggest that stress and voluntary Meth intake can synergize and disrupt cerebrovasculature in a time-dependent manner during abstinence from chronic stress and Meth. Furthermore, COX-2 inhibition may be a viable pharmacological intervention to block vascular changes after Meth exposure.

Toxic Effects of Methamphetamine on Perivascular Health: Co-morbid Effects of Stress and Alcohol Use Disorders

“…A similar study also highlights the role of COX-2 in CUS-Meth mediated dysregulation of the BBB. Natarajan et al reported that rats that underwent a paradigm of 10 days of CUS followed by 7 days of unrestricted Meth self-administration (SA) exhibited decreases in tight junction proteins that were mediated by COX-2 [ 106 ]. This study identified increases in COX-2 and degradation of β-dystroglycan in cortical isolated capillaries at 3 days after the last day of Meth SA that persisted for at least 7 days, at which time point decreases in occludin were also apparent.…”

Brain–body responses to chronic stress: a brief review

“…However, chronic physical and psychosocial stress leads to a significant perturbation of immune responses and can lead to hyper-inflammatory responses, many of which can resemble chronic inflammatory diseases 42 and can even impact cancer progression 43 – 45 . Exciting recent work further demonstrates that chronic stress can result in low brain vasculature and elevated permeability of the blood–brain barrier 46 – 48 , potentially leading to vulnerability in penetration of peripheral immune cell types. Specific effects of chronic stress on the response of several classes of immune cells, including on regulatory T cells, which can protect from adverse stress-induced behaviors when balanced by healthy metabolites of the gut microbiota, have also recently been reported 49 .…”