Bile Acids Regulate Accumbal Cholinergic Circuitry and Dopamine Release through TGR5 Activation

BackgroundFatty foods and alcohol (i.e., ethanol) produce strong reinforcing effects, in part by altering cholinergic interneuron (CIN) activity and tonic dopamine (DA) release within the nucleus accumbens (NAc). Ethanol and fatty foods also both stimulate hepatic and possibly local brain bile acid (BA) synthesis, which raises the possibility that BAs may act as a common upstream regulator of these substances shared mesolimbic effects. MethodsThe current study investigated whether BAs can directly alter mesolimbic activity. Electrophysiological data from acute mouse brain slices was collected to assess BA effects on NAc CIN firing, as well as on excitatory and inhibitory postsynaptic CIN inputs. Bile effects on NAc DA release and clearance rates were measured through voltammetry. ResultsWe found that low concentrations of a 1:1 mixture of BAs cholic acid (CA) and deoxycholic acid (DCA; 1-10 M) increased CIN firing rate, whereas high BA concentrations (1-10 mM) decreased CIN firing. We further demonstrated that BA-induced excitatory effects on CIN firing are independently mediated by at least two mechanisms: Takeda G-protein-coupled receptor 5 (TGR5) activation and suppression of inhibitory CIN currents. Additionally, our results indicate that BAs modulate inhibitory input in a complex manner, reducing frequency at low concentrations, but increasing at high concentrations, and increasing amplitude at low concentrations current amplitude, and the distribution of postsynaptic current amplitude sizes across concentrations. Finally, our voltammetry data indicate that while low BA concentrations enhance NAc DA release without affecting DA uptake, high BA concentrations robustly inhibit accumbal DA release. ConclusionOur findings provide evidence that BAs exert direct modulatory effects on neural activity in the striatum.