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  • Addiction
  • Perturbations of the gut microbiome affect drug seeking behaviors

    • D. D. KIRALY ;
    • E. G. PECK ;
    • A. GODINO ;
    • N. L. MERVOSH ;
    • E. S. CALIPARI ;

    Information from abstracts and lay language summaries is embargoed until the conclusion of the scientific presentation.

    333—Cocaine and Neurotransmission

    Monday, November 13, 2017, 8:00 am - 12:00 noon

    333.09 Perturbations of the gut microbiome affect drug seeking behaviors

    Location: Halls A-C

    1Psychiatry / Neurosci., 2Icahn Sch. of Med. at Mount Sinai, New York, NY; 3Fishberg Dept. of Neurosci., Icahn Sch. of Med. at Mount Sinai, New York City, NY; 4Mount Sinai Sch. of Med., New York, NY

    Abstract Body: The resident bacteria of the gastrointestinal tract, collectively dubbed the gut microbiome, have been shown to have profound effects on both brain and behavior. To date, the majority of research into the effects of the gut microbiome in neuropsychiatric pathology has focused on affective and neurodegenerative disorders. However, we recently demonstrated that altering the gut microbiome has a marked effect on the behavioral and neurobiological responses to cocaine. Animals with depleted gut flora exhibited increased locomotor sensitization and a lower threshold for conditioned place preference for cocaine. Additionally, these mice had altered regulation of the genes encoding brain-derived neurotrophic factor, the D1 dopamine receptor, and other important regulators of behavioral response to cocaine. Here, we utilized a cocaine self-administration paradigm and behavioral economics modeling to assess how shifts in the gut microbiome directly affect motivation to seek and take cocaine. As previously published, we depleted the gut microbiome of rats with a cocktail of broad-spectrum non-absorbable antibiotics via their drinking water for two weeks. These animals were then trained to self-administer cocaine on a fixed-ratio 1 schedule until they were stably administering for five days. Self-administration acquisition rates did not differ between groups. Animals were then assessed using a behavioral economics threshold task, a within-session method used to assess an animal’s motivation to self-administer a reinforcer in the face of increasing cost. Microbiome-depleted rats were insensitive to increases in cost (as measured by effort required) for each milligram of cocaine. This insensitivity to increasing drug cost is analogous to insensitivity to cost seen in human drug abusers. When cue and drug were removed, microbiome-depleted rats exhibited more rapid extinction of lever pressing for cocaine. However, after allowing for an incubation period after completion of extinction, we find that microbiome-depleted rats exhibited enhanced reinstatement for both cue and cocaine stimuli. Taken together, these findings suggest that changes in the gut microbiome can alter motivation to seek drug, and affect how animals update reward contingencies in a complex manner. Molecular studies are currently underway to determine how underlying changes in gene expression and epigenetic regulation lead to this altered behavioral phenotype.

    Lay Language Summary: For many years it has been known that the billions of bacteria that take up residence in the large intestine, collectively known as the gut microbiome, play an important role in intestinal health. Recently, it has been discovered that the gut microbiome and its byproducts are also playing an important role in regulating brain function and behavior. Research from our lab suggests that the gut microbiome may play a key role in the development of cocaine addiction.
    Addiction to cocaine represents a serious public health problem that results in significant costs to the affected individuals, their families, and society at large. Addiction is associated with increased health care costs, decreased workplace productivity, increased unemployment, and a substantially increased risk of early death or permanent injury. Cocaine use disorder in particular affects approximately one million people in the United States. Despite the tremendous toll that cocaine use disorder takes on patients and on society there are currently no FDA-approved medications to treat this condition.
    As mentioned above, the gut microbiome is known to affect brain function in various models of psychiatric disease. Recently, our group published a study demonstrating a role for the gut microbiome in an animal model of cocaine addiction. In this study, we found that animals who had their gut microbiome depleted with chronic antibiotics had altered behavioral response to cocaine and had changes in expression of important neurotransmitter signaling pathways such as dopamine and glutamate. This previous study provided important clues that the gut microbiome may be playing a role in the development of addiction-like behaviors in rodents. However, more detail is needed to make these findings relevant to drug addicted patients.
    In the present study, we utilized a model of cocaine use disorder with high relevance to human addiction. In this model, animals are implanted with an intravenous catheter and we are able to monitor how the animals administer themselves cocaine (referred to as self-administration). The use of this model is important as it allows us to assess factors such as how hard the animals are willing to work to receive cocaine, how much cocaine they take, and assess behaviors in models of relapse.
    We found that animals who had their gut microbiome depleted with antibiotics showed significantly more addiction-like behaviors. In a test in which the animals had to work harder and harder to receive an infusion of cocaine, the animals that lacked a microbiome worked much harder than the control animals. Similarly, when we assessed a model of cocaine-induced drug relapse, we found that the animals with a depleted gut microbiome showed significantly higher relapse-like behaviors. These experiments demonstrate that changes in the gut microbiome can affect both the development of and the persistence of addiction-like behaviors in an animal model.
    This work provides exciting finding that changes in the gut microbiome can affect multiple phases of the addiction process. While these animals showed increases in addiction-like behaviors, we are now working to determine how we can fine-tune the gut microbiome to decrease these behaviors. Future studies will work to examine how the gut microbiome works to affect brain function in models of addiction. By determining how specific bacteria and bacterial products affect brain and behavior, we can begin to perform more targeted studies to manipulate the gut microbiome in a way that will limit the development and/or persistence of addictive disorders. This research has high potential to move from bench to bedside in the form of early stage clinical trials, and may represent the beginnings of an appropriate pharmacotherapy for cocaine use disorder.