Bile acids modulate reinstatement of cocaine conditioned place preference and accumbal dopamine dynamics without compromising appetitive learning

Abstract

Psychostimulants target the dopamine transporter (DAT) to elicit their psychomotor actions. Bile acids (BAs) can also bind to DAT and reduce behavioral responses to cocaine, suggesting a potential therapeutic application of BAs in psychostimulant use disorder. Here, we investigate the potential of BAs to decrease drug-primed reinstatement when administered during an abstinence phase. To do this, after successful development of cocaine-associated contextual place preference (cocaine CPP), cocaine administration was terminated, and animals treated with vehicle or obeticholic acid (OCA). When preference for the cocaine-associated context was extinguished, mice were challenged with a single priming dose of cocaine, and reinstatement of cocaine-associated contextual preference was measured. Animals treated with OCA demonstrate a significantly lower reinstatement for cocaine CPP. OCA also impairs the ability of cocaine to reduce the clearance rate of electrically stimulated dopamine release and diminishes the area under the curve (AUC) observed with amperometry. Furthermore, the AUC of the amperometric signal positively correlates with the reinstatement index. Using operant feeding devices, we demonstrate that OCA has no effect on contextual learning or motivation for natural rewards. These data highlight OCA as a potential therapeutic for cocaine use disorder.

Examining Cognitive Performance in Mice using the Open-Source Operant Feeding Device FED3

“…The FED3 has been successfully implemented in non-operant quantitative feeding studies, but published operant studies largely focused on motivated consumption using fixed or progressive ratio testing procedures [52][53][54][55] . More complex cognitive behavioral testing often requires larger group sizes than traditional feeding studies to achieve significance, indicating a potential data management bottleneck for cognitive behavioral studies utilizing the FED3 where a 40-mouse study could generate over 1000 individual data files.…”