Abstract
Addiction to cocaine and other psychostimulants represents a major public health crisis. The development and persistence of addictive behaviors comes from a complex interaction of genes and environment - the precise mechanisms of which remain elusive. In recent years a surge of evidence has suggested that the gut microbiome can have tremendous impact on behavioral via the microbiota-gut-brain axis. In this study we characterized the influence of the gut microbiota on cocaine-mediated behaviors. Groups of mice were treated with a prolonged course of non-absorbable antibiotics via the drinking water, which resulted in a substantial reduction of gut bacteria. Animals with reduced gut bacteria showed an enhanced sensitivity to cocaine reward and enhanced sensitivity to the locomotor-sensitizing effects of repeated cocaine administration. These behavioral changes were correlated with adaptations in multiple transcripts encoding important synaptic proteins in the brain’s reward circuitry. This study represents the first evidence that alterations in the gut microbiota affect behavioral response to drugs of abuse.
Highlights
Despite this interest in gut-brain connections in mood, anxiety, and autism-related disorders, there has been no published work directly examining the link between changes in gut microbiota and the rewarding properties of drugs of abuse
Reduction of the gut microbiota with prolonged treatment with antibiotics resulted in markedly enlarged ceca (Fig. 1d,e – two-tailed t-test: p < 0.0001; t = 17.7) as has been previously reported in antibiotic-treated and germ-free mice23,24. qPCR analysis of 16S rRNA from cecal contents was demonstrated a 72% reduction in bacterial content in mice treated with broad-spectrum antibiotics (Fig. 1f – two-tailed t-test: p < 0.0001; t = 7.03)
While the antibiotics used to knockdown intestinal bacteria are non-absorbable and are excreted in the feces, the possibility remained that alterations in gut bacteria could alter the expression of hepatic enzymes which are responsible for metabolism of cocaine – thereby altering the effective dose the animal would receive in a weight-based dosing model
Summary
Despite this interest in gut-brain connections in mood-, anxiety-, and autism-related disorders, there has been no published work directly examining the link between changes in gut microbiota and the rewarding properties of drugs of abuse. Several studies have shown altered levels of monoamine metabolism in the brains of mice with reduced gut bacteria3,18,22 – another change that is of critical importance to behavior related to drugs of abuse. To test the hypothesis that alterations in the gut microbiota could affect psychostimulant-induced behavior, we substantially reduced the gut bacteria of a group of mice using antibiotics that are not systemically absorbed from the intestines. After this targeted knockdown of gut bacteria, we examined the mice on tests of cocaine preference and locomotor sensitization. We demonstrate that alterations in gut microbiota significantly affect the dose-response relationship for cocaine and lead to alterations in levels of important synaptic transcripts in the brain’s reward circuitry following cocaine treatment
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