Ethanol intake and ethanol-conditioned place preference are reduced in mice treated with the bioflavonoid agent naringin Amine Bahi a, * , Syed M. Nurulain b , Shreesh Ojha b a Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates b Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates Keywords: Conditioned place preference GW9662 Ethanol Naringin Peroxisome proliferator-activated receptors Two-bottle choice abstract Recently, PPAR-g activation has emerged as a potential treatment for alcoholism. However, the adverse effects of synthetic PPAR-g activators, despite being effective drugs, prompted the need for novel PPAR-g agonists that retain efficacy and potency with a lower potential of side effects. Hence, naringin, a bio- flavonoid isolated from citrus fruits and recently identified as a natural ligand of PPAR-g, has begun to be evaluated for treatment of alcoholism. It is well known to possess several therapeutic benefits in addition to its anti-anxiety and antidepressant properties. In the present study, we assessed whether naringin treatment possesses anti-ethanol reward properties in C57BL/6 mice. We used the two-bottle choice drinking paradigm and ethanol-induced conditioned place preference (CPP) to examine the effect of naringin treatment on ethanol drinking. Results have shown that, compared with vehicle, naringin (10 e100 mg/kg) significantly and dose-dependently decreased voluntary ethanol intake and preference in a two-bottle choice drinking paradigm [3e15% (v/v) escalating over 2 weeks], with no significant effect observed on saccharin [0.02e0.08% (w/v)] or on quinine [15e60 mM (w/v)] intake. In addition, there was no significant difference in blood ethanol concentration (BEC) between groups following naringin administration of 3 g of ethanol/kg body weight. Interestingly, when mice were treated with vehicle or naringin (30 mg/kg) before injection of ethanol (1.5 g/kg) during conditioning days, naringin inhibited the acquisition of ethanol-CPP. More importantly, these effects were significantly attenuated when mice were pre-injected with the peroxisome proliferator-activated receptor-g (PPAR-g) antagonist, GW9662. Taken together, the present findings are the first to implicate naringin and PPAR-g receptors in the behavioral and reward-related effects of ethanol and raise the question of whether specific drugs that target PPAR-g receptors could potentially reduce excessive ethanol consumption and preference. Ó 2014 Elsevier Inc. All rights reserved. Introduction The World Health Organization (WHO) estimates that approxi- mately 2.5 million people die every year from ethanol use. While several therapeutic options are available for the treatment of ethanol dependence, all existing therapies have only modest efficacy. One of the most exciting developments in the treatment of alcoholism was the advent of medications such as naltrexone and acamprosate (Rezvani, Lawrence, Arolfo, Levin, & Overstreet, 2012; Soyka & Rösner, 2010). The development of these medications provided a proof-of-concept for the feasibility of integrated, pharmacologically aided treatment of alcoholism, but also pointed to an urgent need for identifying additional pharmacological approaches, because only a minority of patients benefitted from these drug treatments (Heilig, Goldman, Berrettini, & O’Brien, 2011; Myrick & Anton, 1998). Very recently, peroxisome proliferator-activated receptors (PPARs), which are ligand-activated transcription factors of the nu- clear hormone receptor superfamily, have appeared to be involved in ethanol addiction. PPARs were identified in the neurons, the oligo- dendrocytes, and the astrocytes of the central nervous system (CNS) (Gofflot et al., 2007; Sarruf et al., 2009). Within the 3 distinct PPAR isoforms (PPARa, PPARb/d, and PPAR-g), in particular, PPAR-g is highly expressed in the lateral hypothalamus (LH), the para- ventricular nucleus (PVN) of the hypothalamus, the arcuate nucleus (ARC), and the ventral tegmental area (VTA). In LH and ARC, PPAR-g is expressed in the cells producing a-melanocyte-stimulating hormone (a-MSH), agouti-related protein (AgRP), and pro-opiomelanocortin Abbreviations: CPP, conditioned-place preference; nAChRs, nicotinic acetylcho- line receptors; NAR, naringin; PPAR, peroxisome proliferator-activated receptor; TZD, thiazolidinedione. Disclosure/Conflict of interest: The authors have no financial interests that might be perceived to influence the results or the discussion reported in this article. * Corresponding author. Tel.: þ971 3 7137 516; fax: þ971 3 7672 033. E-mail address: amine.bahi@uaeu.ac.ae (A. Bahi). Contents lists available at ScienceDirect Alcohol journal homepage: http://www.alcoholjournal.org/ http://dx.doi.org/10.1016/j.alcohol.2014.06.008 0741-8329/Ó 2014 Elsevier Inc. All rights reserved. Alcohol 48 (2014) 677e685