Abstract
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.
Highlights
Bile acids have been viewed as detergents participating in the emulsification of ingested fats
Behavioral pharmacological experiments indicate that increased DA transmission is clearly both necessary and sufficient to promote psychostimulant reinforcement, including the development of cocaine place preference (CPP)
Three stable baseline recordings were taken at five-minute stimulation intervals, and no differences were noted between gallbladder is anastomosed to the duodenum (GB-D) (Fig 1C, baseline) and gallbladder to the ileum (GB-IL) (Fig 1C, baseline) in terms of peak amperometric current (Fig 1D)
Summary
Bile acids have been viewed as detergents participating in the emulsification of ingested fats. GB-IL mice exhibit reduced high fat food consumption as well as weight loss. This reduction in the intake of rewarding, calorically dense food could stem at least in part from altered valuation of palatable food. We show that GB-IL surgery is able to alter the behavioral and pharmacological responses to cocaine This led us to uncover a novel role of central bile acid signaling mediated by Takeda G protein-coupled bile acid receptor (TGR5) for cocaine-induced impairments in DA homeostasis and the development of associated behaviors
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