Peroxisome proliferator-activated receptor (PPAR) agonists as promising new medications for drug addiction: preclinical evidence

Abstract

This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together these preclinical data indicate that PPAR agonists are promising new medications for drug addiction treatment.

Figure 1

Biological effects of PPARs. CB: cannabinoid receptor; 2-AG: 2-arachindonoylglycerol; AEA: anandamide; FAAH: fatty acid amide hydrolase; OEA: oleoylethanolamide; PEA: palmitoylethanolamide; PPAR: peroxisome proliferator activated receptor

Figure 2

Clofibrate prevented the acquisition of nicotine self-administration in nicotine-naïve rats. Left panel: Vehicle-treated control rats acquired nicotine self-administration and responses in the active nose-poke hole were greater than in the inactive nose-poke hole that had no consequences. Right panel: Clofibrate pre-treatment decreased the acquisition of nicotine self-administration; responses in the inactive and active nose-poke holes were the same. Taken from Panlilio et al. (2012).

Figure 3

Reinstatement of nicotine-seeking by a priming injection of nicotine after extinction in monkeys. The PPAR-α agonist WY14643 (20 or 40 mg/kg i.p.) dose-dependently reduced the reinstatement of extinguished nicotine-seeking responses. This effect of WY14643 was prevented by pretreatment with the PPAR-α antagonist MK886 (1 mg/kg i.m.). Data are presented as mean ± SEM. *Significant difference from vehicle pretreatment during a saline prime session. #Significant difference from vehicle pretreatment during a nicotine prime session. Taken from Masica et al. (2011).

Figure 4

The effect of pioglitazone on yohimbine-induced reinstatement (left panel) and cue-induced reinstatement (right panel). During training, rats consumed alcohol prior to extinction (Ext) of this response. Compared with extinction, both yohimbine (left panel) and cues predictive of alcohol (S+; right panel) induced reinstatement of alcohol-seeking. Responding for the alcohol-predictive cues (S+) was also higher than responding for a stimulus predictive of water availability (S−). Yohimbine-induced reinstatement was reduced following treatment with pioglitazone (Pio), while cue-induced reinstatement was not affected. *Significant difference from vehicle (p<0.05 for yohimbine-induced reinstatement and p<0.01 for the cue-induced reinstatement data). Data are presented as mean ± S.E.M. Taken from Stopponi et al. (2011).