PPAR Agonists: I. Role of Receptor Subunits in Alcohol Consumption in Male and Female Mice

Background Several peroxisome proliferator‐activated receptor ( PPAR ) agonists reduce voluntary alcohol consumption in rodent models, and evidence suggests that PPAR α and γ subunits play an important role in this effect. To define the subunit dependence of this action, we tested selective PPAR α and α / γ agonists and antagonists in addition to null mutant mice lacking PPAR α . Methods The effects of fenofibrate ( PPAR α agonist) and tesaglitazar ( PPAR α / γ agonist) on continuous and intermittent 2‐bottle choice drinking tests were examined in male and female wild‐type mice and in male mice lacking PPAR α . We compared the ability of MK 886 ( PPAR α antagonist) and GW 9662 ( PPAR γ antagonist) to inhibit the effects of fenofibrate and tesaglitazar in wild‐type mice. The estrogen receptor antagonist, tamoxifen, can inhibit PPAR γ ‐dependent transcription and was also studied in male and female mice. Results Fenofibrate and tesaglitazar reduced ethanol (EtOH) consumption and preference in wild‐type mice, but these effects were not observed in mice lacking PPAR α . MK 886 inhibited the action of fenofibrate, but not tesaglitazer, while GW 9662 did not inhibit either agonist. The PPAR agonists were more effective in male mice compared to females, and drinking in the continuous 2‐bottle choice test was more sensitive to fenofibrate and tesaglitazar compared to drinking in the intermittent access test. Tamoxifen also reduced EtOH consumption in male mice and this action was inhibited by GW 9662, but not MK 886, suggesting that it acts by activation of PPAR γ . Conclusions Our study using selective PPAR agonists, antagonists, and null mutant mice indicates a key role for PPAR α in mediating reduced EtOH consumption by fenofibrate and tesaglitazar.