Date of Award

12-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Kyle Frantz

Second Advisor

Benoit Chassaing

Abstract

Drug addiction is an intractable psychiatric disorder exerting deleterious impact on public health in the United States and beyond. While the neurobiology of addiction has become clearer over the last few decades, addiction therapies remain largely ineffective. Given recent evidence that a gut-brain axis might influence neuropsychiatric disorders, we explored possible links between gut bacteria and cocaine-related behavior. We hypothesized that gut microbial communities and cocaine intake are linked in such way that microbiota profiles can predict susceptibility to drug use and that drug use alters microbiota composition to enhance drug reward, hence resulting in a vicious cycle of drug use and abuse. Furthermore, although adolescence is a developmental stage associated with high rates of experimentation with drugs of abuse, adolescence is also a period associated with resilience to aversive stimuli. Thus, we predicted that adolescents would be protected from this vicious cycle. Adolescent and adult male Wistar rats were tested in the intravenous cocaine self-administration model, while their fecal samples were analyzed for bacterial abundance (qPCR) and microbiota profiles (NextGen Sequencing of 16S rRNA). With adult rats, experimentation revealed distinct microbiota profiles among low vs. high responders to cocaine reward and reinforcement, especially after long-access cocaine self-administration. Moreover, the relative abundance of two specific microbial groups at baseline predicted low vs. high addiction vulnerability, perhaps warranting investigation as biomarkers of addiction. After establishing a new white noise training procedure and confirming adolescent resistance to an aversive white noise stimulus, we also manipulated the microbiota to reveal that antibiotic-induced gut microbial depletion increased cue-induced reinstatement of cocaine-seeking after abstinence in a model of drug relapse. Yet this effect was observed only in adult rats, not adolescent-onset groups. Treatment with a probiotic formulation during abstinence rescued normal levels of reinstatement in adult rats, suggesting that probiotics may be effective adjunctive therapies for addiction. Overall, this body of work provides another example of adolescent resilience to the enduring effects of physiological perturbations. This work also supports an important role for the gut-brain axis in drug reward and reinforcement, ultimately suggesting new treatment approaches for addiction.

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