Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward

<div><p>The gut-to-brain axis exhibits significant control over motivated behavior. However, mechanisms supporting this communication are poorly understood. We reveal that a gut-based bariatric surgery chronically elevates systemic bile acids and attenuates cocaine-induced elevations in accumbal dopamine. Notably, this surgery reduces reward-related behavior and psychomotor sensitization to cocaine. Utilizing a knockout mouse model, we have determined that a main mediator of these post-operative effects is the Takeda G protein-coupled bile acid receptor (TGR5). Viral restoration of TGR5 in the nucleus accumbens of TGR5 knockout animals is sufficient to restore cocaine reward, centrally localizing this TGR5-mediated modulation. These findings define TGR5 and bile acid signaling as pharmacological targets for the treatment of cocaine abuse and reveal a novel mechanism of gut-to-brain communication.</p></div

Bile diversion to the ileum blocks cocaine locomotor sensitization and reduces cocaine CPP.

<p>(<b>A</b>) Mice underwent surgery (GB-D or GB-IL), recovered for 2 weeks, and began the cocaine CPP paradigm. (<b>B</b>) Average group locomotor activity in CPP chambers during four cocaine exposures (20 mg/kg, i.p.) with linear regression of activity over the four exposures. There was a significant effect of time (Time: F[<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2006682#pbio.2006682.ref003" target="_blank">3</a>, 69] = 2.916; <i>p</i> < 0.043), and treatment × time interaction (F[<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2006682#pbio.2006682.ref003" target="_blank">3</a>, 69] = 2.868; <i>p</i> < 0.041) (<i>n</i> = 11–14; <i>p</i> < 0.05 by two-way repeated measuresANOVA) with a significant difference between cocaine exposure 1 and 4 in GB-D surgery animals (<i>p</i> < 0.003 by multiple comparison tests). (<b>C</b>) Cocaine CPP expressed as percent CPP normalized to GB-D average (<i>n</i> = 13–14; *<i>p</i> < 0.05 by Student <i>t</i> test). (<b>D</b>) OF locomotion. GB-IL mice exhibit a no difference in basal locomotion with reduced response to cocaine (<i>n</i> = 8–10; <i>p</i> < 0.05 by two-way repeated measures ANOVA, F[<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2006682#pbio.2006682.ref001" target="_blank">1</a>, <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2006682#pbio.2006682.ref016" target="_blank">16</a>] = 6.544; *<i>p</i> < 0.05; ***<i>p</i> < 0.001 by multiple comparison test). (inset) AUC for cocaine locomotor responses in GB-D and GB-IL mice (**<i>p</i> < 0.01 by Student <i>t</i> test). Underlying data can be found in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2006682#pbio.2006682.s006" target="_blank">S1 Data</a>. AUC, area under the curve; CPP, conditioned place preference; GB-D, gallbladder to duodenum diversion; GB-IL, gallbladder to ileum diversion; OF, open field.</p