Colon dysregulation in methamphetamine self-administering HIV-1 transgenic rats

Abstract

The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not known. To shed light on this scenario, we evaluated colon barrier pathology in a rat model of the human comorbid condition. Intestinal barrier integrity and permeability were assessed in drug-naïve Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats, and in Tg and non-Tg rats instrumented with jugular cannulae trained to self-administer methamphetamine or serving as saline-yoked controls. Intestinal permeability was determined by measuring the urine content of orally gavaged sugars. Intestinal barrier integrity was evaluated by immunoblotting or immunofluorescence of colon claudin-1 and zonula occludens-1 (ZO-1), two major tight junction proteins that regulate gut epithelial paracellular permeability. Both non-Tg and Tg rats self-administered moderate amounts of methamphetamine. These amounts were sufficient to increase colon permeability, reduce protein level of claudin-1, and reduce claudin-1 and ZO-1 immunofluorescence in Tg rats relative to non-Tg rats. Methamphetamine decreased tight junction immunofluorescence in non-Tg rats, with a similar, but non-significant trend observed in Tg rats. However, the effect of methamphetamine on tight junction proteins was subthreshold to gut leakiness. These findings reveal that both HIV-1 proteins and methamphetamine alter colon barrier integrity, and indicate that the gut may be a pathogenic site for these insults.

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].…”

Antibiotic-Driven Gut Microbiome Disorder Alters the Effects of Sinomenine on Morphine-Dependent Zebrafish

“…Methamphetamine can destroy the blood-brain barrier, leading to increased blood-brain barrier permeability and to a reduced expression of tight junction protein, which then induces neuroinflammation ( Martins et al, 2011 ; Northrop and Yamamoto, 2015 ; Turowski and Kenny, 2015 ). Furthermore, this drug can also reduce the level of ZO-1 protein in the rat colon and change colon permeability ( Persons et al, 2018 ). In this study, compared with the C group, the expression levels of occludin a and occludin b mRNAs in the zebrafish brain and intestine were significantly reduced in the M group.…”

Evaluation of Microglia/Macrophage Cells from Rat Striatum and Prefrontal Cortex Reveals Differential Expression of Inflammatory-Related mRNA after Methamphetamine

“…Along these lines, Figures 3 and 4 illustrate that METH changes expression for a number of genes involved in directing arachidonic acid metabolism toward PGE2 production that could be dependent on LPS derived from a leaky gut. In fact, Persons et al [56] showed that METH self-administration in Fischer 344 rats resulted in lower expression of gut tight junction proteins claudin-1 and ZO-1 as well as a morphological disorganization of these proteins in the colon. Additionally, human METH users suffer from bowel ischemia which is associated with loss of gut integrity [57,58] that may lead to the entry of LPS into the brain parenchyma as shown in rats following a METH-induced compromise of the blood-brain-barrier [59].…”