Browsing by Author "Forouzan, Shadab"
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Item BEHAVIORAL AND MICROBIAL CONSEQUENCES OF METHAMPHETAMINE EXPOSURE AND WITHDRAWAL IN RATS(2022-05) Forouzan, Shadab; Kosten, Therese A.; Meisch, Richard A.; Alward, Beau A.; Hoffman, Kristi LouiseRationale: Methamphetamine use disorder (MuD) continues to be a global health problem that results in behavioral changes associated with addiction and neurocognitive decline. Despite the profound burden of this disorder, currently, there are no FDA-approved medications for the treatment of MuD. Accumulative evidence reveals the influence of gut microbiota on the brain, behavior, and health as a part of the gut-brain axis but its involvement in modulating this substance use disorder remains poorly understood. Objective: We sought to determine whether methamphetamine exposure and withdrawal alter the intestinal gut microbiota and characterize withdrawal-induced behavioral changes in male and female rodents. We also sought to explore whether the administration of probiotics alters gut microbial composition and blocks the development of anxiety- and depressive-like behavior in METH-exposed male and female rats. Methods: Male and female Sprague-Dawley rats were administered methamphetamine injections (2 mg/kg; s.c.) or saline injection twice daily with either a combination of probiotics or placebo solution (4 groups/n=8 per group) for 14 consecutive days. On various days before, during, and after administration, fecal samples were collected, and tests of anxiety- and depressive-like behaviors were conducted. Results: Methamphetamine exposure and its withdrawal altered gut microbial composition; and induced anxiety-like behavior in females and anxiety- and depressive-like behavior in males. Two weeks of supplementation with Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 blocked the development of methamphetamine-induced anxiety- and depressive-like behavior in males and restored gut microbial composition more in females. Conclusions: These findings provide direct evidence that methamphetamine and its withdrawal cause gut dysbiosis in both sexes and that the latter is associated with anxiety- and depressive-like behavior in males. The alternative therapies such as probiotics hold potential in treating METH-induced behavioral changes and restoring gut microbial composition in a sex-specific manner. Our observations will contribute to a better understanding of the function of gut microbiota in the process of substance use disorders and guide the choice of target therapeutics.Item Methamphetamine Exposure and Withdrawal Impact Gut Microbiota and Induce Depressive-Like Behavioral Effects on Rodents.(2019-05) Forouzan, Shadab; Kosten, Therese A.; Lee, Sunbok; Meisch, Richard A.Methamphetamine (MA) is one of the most frequently used amphetamine-type stimulants in the United States. Individuals who repeatedly abuse MA can develop MA use disorder (MuD)—a chronic, relapsing condition often triggered by withdrawal symptoms that develop following cessation of use. Long term abuse MA can result in negative health consequences including extreme weight loss, severe dental problems, malnutrition, confusion, insomnia, mood disturbances, and violent behavior. Importantly, depression and anxiety are key diagnostic characteristics of MA withdrawal in humans. Despite the well-documented dangers of chronic MA use, approximately 1.2 million people reported using MA in the past year. Given the lack of effective treatments for those with MuD, novel therapeutic targets must be considered. One potential target is the gut microbiome, which has an important influence on brain, behavior, and health as a part of the gut-brain axis. The gut microbiome comprises microorganisms and their genomes that reside in the intestinal tract. Therefore, the use of psychobiotics may provide a new way for treatments for drug addiction. In this study, we evaluated the effects of MA administration (2 mg/kg, s.c.) on withdrawal- induced behaviors and in the gut microbiota in male Sprague-Dawley rats (n=8). 16 male rats (60-70 days old) were divided equally into 2 groups: METH and Vehicle (control) groups. Rats in METH group were given twice daily injection of Saline (s.c) for 14 days, during which baseline behaviors (elevated plus maze (EPM) for anxiety-like behavior; forced swim test (FST) for depressive-like behavior) were assessed. Next, rats were given twice daily injections of MA for 14 days, followed by 7 days of withdrawal, during which performance on the Elevated Plus Maze (EPM), Open Field Task (OFT), and Forced Swim Task FST were assessed. Control group were given twice daily injection of Saline (s.c.) for 28 days, followed by 7 days of withdrawal. Fecal collection for microbiome analyses occurred on day 5 of saline administration, day 1, 7, 14 of MA administration, at 24-, 48- and 96-h, and day 7 of withdrawal, during which performance on the EPM, OFT, and FST were assessed. Results indicated that MA withdrawal increased depressive-like behavior, with an increase in immobility time in the FST (p<0.05). Anxiolytic/anxiogenic effects were not observed in either group. We analyzed the gut microbiome composition of each group through 16S rRNA gene sequencing. Results revealed MA administration and withdrawal significantly changed the relative abundances of several bacterial phyla. Compared to control group, the METH group demonstrated a higher abundance of Firmicutes, Verrumcomicrobia, Actinobacteria, Tenericutes, and Proteobacteria (p <0.05, vs. saline), and lower abundance of Bacteroidetes (p <0.05, vs. saline). At the genus level, Allobaculum, Bifidobacterium, and Lactobacillus were significantly more abundant in the fecal microbiota of METH group than vehicle group during MA administration and early days of withdrawal and they were normalized completely after 7 days of withdrawal. No significant changes in Shannon diversity were observed. These findings provide direct evidence that administration of MA causes gut dysbiosis and withdrawal from chronic methamphetamine induces depressive-like but not anxiety-like behavioral effects in male rodents. Our observation will contribute to a better understanding of the function of gut microbiota in the process of drug abuse and guide the choice of target therapeutics for MuD to test in future studies.