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

Abstract

Background Several peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary alcohol consumption in rodent models, and evidence suggests that PPARα and γ subunits play an important role in this effect. To define the subunit dependence of this action, we tested selective PPARα and α/γ agonists and antagonists in addition to null mutant mice lacking PPARα. Methods The effects of fenofibrate (PPARα agonist) and tesaglitazar (PPARα/γ agonist) on continuous and intermittent two-bottle choice drinking tests were examined in male and female wild-type mice and in male mice lacking PPARα. We compared the ability of MK886 (PPARα antagonist) and GW9662 (PPARγ antagonist) to inhibit the effects of fenofibrate and tesaglitazar in wild-type mice. The estrogen receptor antagonist, tamoxifen, can inhibit PPARγ-dependent transcription and was also studied in male and female mice. Results Fenofibrate and tesaglitazar reduced ethanol consumption and preference in wild-type mice, but these effects were not observed in mice lacking PPARα. MK886 inhibited the action of fenofibrate, but not tesaglitazer, while GW9662 did not inhibit either agonist. The PPAR agonists were more effective in male mice compared to females, and drinking in the continuous two-bottle choice test was more sensitive to fenofibrate and tesaglitazar compared to drinking in the intermittent access test. Tamoxifen also reduced ethanol consumption in male mice and this action was inhibited by GW9662, but not MK886, suggesting that it acts by activation of PPARγ. Conclusions Our study using selective PPAR agonists, antagonists, and null mutant mice indicates a key role for PPARα in mediating reduced ethanol consumption by fenofibrate and tesaglitazar.

The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration in rats

“…For example, Ferguson et al showed pretreatment with fenofibrate (150mg/kg/8 days, PO) decreased EtOH (15%) consumption in mice using a continuous access two-bottle choice drinking procedure (Ferguson et al, 2014). A more recent study showed similar results following fenofibrate (100 and 150mg/kg, PO) administration in mice using continuous and intermittent 2-bottle choice EtOH (15%) drinking tests (Blednov et al 2016a). In that same study, fenofibrate administration in mice lacking PPARα did not alter EtOH consumption but did in wild-type mice thus showing specificity.…”

“…Recent studies have shown the PPARα agonist fenofibrate (a pro-drug for fibrinic acid) decreases voluntary EtOH consumption in mice (Blednov et al, 2016; Ferguson et al, 2014) and rats (Karahanian et al, 2014). Similarly, gemfibrozil, a PPARα partial agonist, also decreases voluntary EtOH intake in rats (Barson et al, 2009).…”

Preclinical Medication Development: New Targets and New Drugs

“…Fenofibrate, tesaglitazar, and pioglitazone also significantly altered multiple behaviors associated with alcohol consumption. Blednov et al (2016a) demonstrated decreased novelty-induced locomotion, reduced ethanol-induced loss of righting reflex, reduced ethanol withdrawal symptoms, and enhanced ethanol metabolism with some sex differences. Neither fenofibrate nor tesaglitazar reduced ethanol-induced CPP.…”

“…Pioglitazone reduced operant responses for ethanol, but not saccharin, reduced yohimbine-induced (but not cue-induced) ethanol reinstatement, and reduced ethanol withdrawal scores independent of PPARα activation (Stopponi et al, 2011). Although the ability of PPAR agonists to reduce drinking appears to be dependent on presence of the α subunit, the γ subunit may be critical for enhancing the effects of PPARα agonists on alcohol-related behaviors (Stopponi et al, 2011; Blednov et al, 2016a; 2016b). …”

Genes and Alcohol Consumption

“…Several FDA-approved drugs with anti-inflammatory and immune inhibitory effects regulate alcohol responses in animal models, lending support that some of these could potentially be repurposed to treat AUD. For example, the peroxisome proliferator-activated receptor (PPAR) agonists, fenofibrate and tesaglitizar, reduced drinking in a PPARα-dependent manner (Blednov, Black, Benavidez, Stamatakis, & Harris, 2016), altered expression of immune genes in the liver, and altered neuronal gene expression in mouse brain (Ferguson, Most, Blednov, & Harris, 2014). There is overlapping evidence in mice and humans for specific PPAR genes in alcohol consumption and dependence (Blednov, Benavidez, Black, Ferguson, et al, 2015).…”