Biology subjects

Maturin, L.

Publications and source records attributed to Maturin, L..

4 recordsLinked to original sources

bioRxiv2021

Individual differences in members of Actinobacteria, Bacteroidetes, and Firmicutes is associated with resistance or vulnerability to addiction-like behaviors in heterogeneous stock rats

An emerging element in psychiatry is the gut-brain-axis, the bi-directional communication pathways between the gut microbiome and the brain. A prominent hypothesis, mostly based on preclinical studies, is that individual differences in the gut microbiome composition and drug-induced dysbiosis may be associated with vulnerability to psychiatric disorders including substance use disorder. However, most studies used small sample size, ignored individual differences, or used animal models with limited relevance to addiction. Here, we test the hypothesis that pre-existing microbiome composition and drug-induced changes in microbiome composition can predict addiction-like behaviors using an advanced animal model of extended access to cocaine self-administration in a large cohort of heterogenous stock (HS) rats. Adult male and female HS rats were allowed to self-administer cocaine under short (2h/day) and long access (6h/day) for ~7 weeks under various schedule of reinforcement to identify individuals that are resistant or vulnerable to addiction-like behaviors and fecal samples were collected before the first session and after the last session to assess differences in the microbiome composition. Linear discriminant analysis (LDA) identified sex-dependent and sex-independent differences at the phylum, order, and species level that are differentially abundant in resistant vs. vulnerable individuals, including high level of actinobacteria both before the first exposure to cocaine and after 7 weeks of cocaine self-administration in resistant animals. Predictions of functional gene content using PICRUSt revealed differential regulation of short-chain fatty acid processing in the vulnerable group after self-administration. These results identify microbiome constituents as well as metabolic pathways that are associated with resistance or vulnerability to addiction-like behaviors in rats. Identification of microbes and tangential metabolic pathways involved in cocaine resilience/vulnerability may represent an innovative strategy for the development of novel biomarkers and medication for the treatment of cocaine use disorder.

animal behavior and cognition↗

bioRxiv2021

Characterization of cocaine addiction-like behavior in heterogeneous stock rats

Addiction is commonly characterized by escalation of drug intake, compulsive drug seeking, and continued use despite harmful consequences. However, the factors contributing to the transition from moderate drug use to these problematic patterns remain unclear, particularly regarding the role of sex. Many preclinical studies have been limited by small sample sizes, low genetic diversity, and restricted drug access, making it challenging to model significant levels of intoxication or dependence and translate findings to humans. To address these limitations, we characterized addiction-like behaviors in a large sample of >500 outbred heterogeneous stock (HS) rats using an extended cocaine self-administration paradigm (6 h/daily). We analyzed individual differences in escalation of intake, progressive-ratio (PR) responding, continued use despite adverse consequences (contingent foot shocks), and irritability-like behavior during withdrawal. Principal component analysis showed that escalation of intake, progressive ratio responding, and continued use despite adverse consequences loaded onto a single factor that was distinct from irritability-like behaviors. Categorizing rats into resilient, mild, moderate, and severe addiction-like phenotypes showed that females exhibited higher addiction-like behaviors, with a lower proportion of resilient individuals compared to males. These findings suggest that, in genetically diverse rats with extended drug access, escalation of intake, continued use despite adverse consequences, and PR responding are highly correlated measures of a shared underlying construct. Furthermore, our results highlight sex differences in resilience to addiction-like behaviors.

neuroscience↗

bioRxiv2021

Leptin protects against the development and expression of cocaine addiction-like behavior in heterogenous stock rats

In addition to its pleasurable effects, weight control is a significant contributor to initiation, maintenance and relapse of cocaine use. This suggests that individual differences in bodyweight control and feeding hormones, such as leptin may contribute to the vulnerability to cocaine use disorder. While pre-clinical studies have shown a mutually inhibitory relationship between leptin and cocaine, they have used small sample sizes and did not investigate individual differences in a large heterogeneous population. Here, we tested if individual differences in bodyweight and blood leptin level is associated with high or low vulnerability to addiction-like behaviors using data from 500 heterogenous stock rats and 160 blood samples from the Cocaine Biobank, using a model of extended access to intravenous self-administration of cocaine. Finally, we tested a separate cohort to evaluate the causal effect of exogenous leptin administration on cocaine seeking. Bodyweight, while changing due to cocaine self-administration in males, was not related to the vulnerability to addiction-like behavior. Blood leptin levels after ~6 weeks of cocaine self-administration did not correlate with addiction-like behaviors, however, baseline blood leptin levels before any access to cocaine negatively predicted addiction-like behavior. Finally, administration of leptin reduced cocaine intake after acute withdrawal and cocaine seeking after 6 weeks of protracted abstinence. These results demonstrate that high blood leptin level before access to cocaine may be a protective factor against the development of cocaine addiction-like behavior, that exogenous leptin reduces the motivation to take and seek cocaine, but that blood leptin level and bodyweight changes in current users are not good biomarkers for addiction-like behaviors.

physiology↗

bioRxiv2021

The gut microbiome is associated with cocaine behavior and predicts addiction vulnerability in adult male rats

The gut-brain axis is a bi-directional communication system through which microbial communities in the gut interact with the nervous system, perhaps influencing neuropsychiatric disorders such as drug abuse. This study used behavioral data and biological samples from the Cocaine Biobank to test the hypothesis that the gut microbiota can predict and reflect susceptibility to cocaine reinforcement. Adult male heterogenous rats were catheterized and allowed to self-administer cocaine in short-access sessions (2 hr/day, 10 days, 0.5 mg/kg per intravenous infusion), followed by progressive ratio (PR) tests, long-access sessions (6 hr/day, 14 days), and alternating blocks of PR, long-access, and footshock testing. Fecal samples were collected at three time points and bacterial 16s rRNA genes were sequenced to profile the microbiota. As expected, cocaine-related behavior varied among subjects, such that a quartile split identified low and high responders on each measure, as well as an overall addiction index. Although beta diversity in the microbiota at baseline and after short access did not predict membership in high or low addiction quartiles, linear discriminant analysis (LDA) identified taxa that were more robustly represented in low or high responders. Beta diversity after long access was different among quartiles, as were several specific taxa. Investigation of baseline differences revealed that high relative abundance of Akkermansia muciniphila predicted future low response rates, whereas Ruminococcaceae predicted high response. This study is the first to report that microbiota variability reflects levels of cocaine intake and that microbial profiles might facilitate diagnosis and identify risk factors predictive of drug vulnerability. Significance StatementMicrobial organisms inhabiting the gut of animals appear to influence organismal function through various signaling pathways, ultimately affecting behavior and disease vulnerability. This experiment investigates links between gut bacteria and vulnerability to addiction-related behaviors in adult male rats. Not only did gut bacterial profiles change as a result of cocaine intake but also gut bacterial profiles before any exposure to cocaine predicted which animals would be high or low addiction-prone individuals. These results suggest that microbial profiles might facilitate diagnosis and identify risk factors predictive of drug addiction.

neuroscience↗