Effects of fisetin on ethanol-induced rewarding properties in mice.

Background: Alcohol use disorder (AUD) is a chronic relapsing disorder associated with compulsive drinking of alcohol. Natural flavonoid fisetin affects a variety of transmitter systems relevant to AUD, such as aminobutyric acid, N-methyl-D-aspartate, and dopamine, as well as peroxisome proliferator-activated receptors. Objectives: This study investigated fisetin's impact on the motivational properties of ethanol using conditioned place preference (CPP) in mice ( n  = 50). Methods: Mice were conditioned with ethanol (2 g/kg, i.p.) or saline on alternating days for 8 consecutive days and were given intragastric (i.g.) fisetin (10, 20, or 30 mg/kg, i.g.), 45 min before ethanol conditioning. During extinction, physiological saline was injected to the control and ethanol groups, and fisetin was administered to the fisetin groups. To evaluate the effect of fisetin on the reinstatement of ethanol-induced CPP, fisetin was given 45 min before a priming dose of ethanol (0.4 g/kg, i.p.; reinstatement test day). Results: Fisetin decreased the acquisition of ethanol-induced CPP (30 mg/kg, p  < .05) and accelerated extinction (20 and 30 mg/kg, p  < .05). Furthermore, fisetin attenuated reinstatement of ethanol-induced CPP (30 mg/kg, p  < .05). Conclusions: Fisetin appears to diminish the rewarding properties of ethanol, as indicated by its inhibitory effect and facilitation of extinction in ethanol-induced CPP. These findings imply a potential therapeutic application of fisetin in preventing ethanol-seeking behavior, promoting extinction, and reducing the risk of relapse.