Following fenofibrate treatment, mice treated with ethanol show marked increases in blood acetaldehyde (Karahanian et al., 2014), suggesting that PPARα-dependent effects on ethanol consumption are mediated by increased systemic levels of acetaldehyde. PPARγ activation by pioglitazone reduces ethanol drinking in genetically selected P rats, and when combined with naltrexone, an even more potent reduction is observed (Stopponi et al., 2013). These effects are blocked by injection of a selective PPARγ antagonist into a lateral cerebral ventricle, indicating a central mechanism of pioglitazone to decrease drinking (Stopponi et al., 2011). Pioglitazone also reduces ethanol consumption in mice, but only for 6 h after injection (Blednov et al., 2014a). Pioglitazone may further protect against neuronal and cognitive degeneration following binge ethanol exposure (Cippitelli et al., 2017) by rescuing ethanol-induced impairments in reversal and spatial learning and inhibiting expression of pro-inflammatory cytokines and neurodegeneration.
