PPAR agonists may have limited ability to reach the brain in rodents (Dasgupta et al., 2007; Weil et al., 1988). We show that although brain levels of the active metabolite of fenofibrate are lower than those in liver and plasma, fenofibric acid does reach mouse brain 2 hours after a single oral treatment. The brain levels attained are likely high enough to activate PPARα but not other PPARs (Willson et al., 2000). Fenofibric acid reaches near maximal levels in brain, liver, and plasma after a single injection, and we also show that the effect of fenofibrate on ethanol consumption does not increase with repeated injections. As mentioned previously, all PPAR isoforms are expressed in the CNS and the overall PPAR activity in the brain is high. The effects of pioglitazone and rosiglitazone on ethanol drinking are blocked by a selective PPARγ antagonist injected into the lateral cerebroventricle, indicating a direct action of PPAR agonists in rat brain (Stopponi et al., 2011). In addition, systemic administration of PPAR agonists produces CNS effects, including improvement of cognitive function (Bhateja et al., 2012),
