PRECLINICAL EVALUATION OF SODIUM BUTYRATE'S POTENTIAL TO REDUCE ALCOHOL CONSUMPTION: A DOSE ESCALATION STUDY IN C57BL/6J MICE IN ANTIBIOTIC-ENHANCED BINGE-LIKE DRINKING MODEL.

INTRODUCTION: In our earlier efforts to establish gut-brain axis during alcohol use disorder (AUD), we have demonstrated that supplementation of C57BL/6J male mice with 8 mg/ml sodium butyrate, a major short-chain fatty acid, in drinking water reduced ethanol intake and neuroinflammatory response in antibiotic (ABX)-enhanced voluntary binge-like alcohol consumption model, drinking in the dark (DID). METHODS: To further evaluate the pre-clinical potential of SB, we have set a dose-escalation study in C57BL/6J male mice to test effects of ad libitum 20 mg/ml SB (SB20) and 50 mg/ml SB (SB50) and their combinations with ABX in the DID procedure for 4 weeks. Effects of these SB concentrations on ethanol consumption and bodily parameters were determined for the duration of the treatments. At the end of study, blood, liver and intestinal tissues were collected to study any potential adverse effects ad to measure blood ethanol concentrations. RESULTS: Increasing SB concentrations in the drinking water caused a loss in the protective effect against ethanol consumption and produced adverse effects on body and liver weights, reduced overall liquid intake. The hypothesis that these effects were due to aversion to SB smell/taste at these high concentrations were further tested in a follow up proof-of-concept study with intragastric gavage administration of SB. The higher gavage dose (320 mg/kg) caused reduction in ethanol consumption without any adverse effects. CONCLUSION: Overall, these findings added more support for the therapeutic potential of SB in management of AUD, given a proper form of administration.

Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function.

Ivermectin (IVM) is a commonly prescribed antiparasitic treatment with pharmacological effects on invertebrate glutamate ion channels resulting in paralysis and death of invertebrates. However, it can also act as a modulator of some vertebrate ion channels and has shown promise in facilitating L-DOPA treatment in preclinical models of Parkinson's disease. The pharmacological effects of IVM on dopamine terminal function were tested, focusing on the role of two of IVM's potential targets: purinergic P2X4 and nicotinic acetylcholine receptors. Ivermectin enhanced electrochemical detection of dorsal striatum dopamine release. Although striatal P2X4 receptors were observed, IVM effects on dopamine release were not blocked by P2X4 receptor inactivation. In contrast, IVM attenuated nicotine effects on dopamine release, and antagonizing nicotinic receptors prevented IVM effects on dopamine release. IVM also enhanced striatal cholinergic interneuron firing. L-DOPA enhances dopamine release by increasing vesicular content. L-DOPA and IVM co-application further enhanced release but resulted in a reduction in the ratio between high and low frequency stimulations, suggesting that IVM is enhancing release largely through changes in terminal excitability and not vesicular content. Thus, IVM is increasing striatal dopamine release through enhanced cholinergic activity on dopamine terminals.