Fenofibrate restores glutamatergic and dopaminergic homeostasis in the nucleus accumbens and reduces alcohol relapse in rats.

Alcohol use disorder (AUD) is associated with dysregulation of glutamatergic and dopaminergic signaling within the nucleus accumbens (NAc), contributing to withdrawal syndrome, craving, and relapse. Fenofibrate, an agonist of the peroxisome proliferator-activated receptor alpha (PPARα), reduces alcohol intake; however, its effects on NAc neurotransmission and the relative contributions of central versus peripheral mechanisms remain unclear. Here, we investigated whether fenofibrate administration initiated during alcohol withdrawal and continued throughout reaccess reduces relapse drinking, and whether this effect involves normalization of glutamate and dopamine in the NAc. Fenofibrate treatment during withdrawal produced a sustained reduction in alcohol consumption throughout a 14-day relapse period in high-drinker female rats. This effect was abolished by systemic co-administration of the PPARα antagonist GW6471. Fenofibrate increased hepatic catalase activity and upregulated the glutamate transporter GLT-1 in the NAc, while dopamine transporter (DAT) protein levels remained unchanged. When GW6471 was administered intracerebroventricularly to block central PPARα activation selectively, the reduction in alcohol intake was only partially attenuated, indicating that approximately one-third of fenofibrate's effect is centrally mediated, whereas two-thirds result from peripheral mechanisms. No-net-flux microdialysis showed that fenofibrate enhanced uptake rates for both glutamate and dopamine in the NAc. Steady-state extracellular glutamate levels were unchanged, whereas extracellular dopamine levels were significantly reduced, consistent with increased functional DAT activity. These findings demonstrate that fenofibrate reduces relapse-like alcohol consumption through a combination of peripheral and CNS PPARα-dependent mechanisms, restoring key aspects of glutamatergic and dopaminergic homeostasis in the NAc, highlighting PPARα activation as a promising therapeutic strategy for AUD.