Novel Use of a Lipid-Lowering Fibrate Medication to Prevent Nicotine Reward and Relapse: Preclinical Findings

Abstract

Experimental drugs that activate a-type peroxisome proliferator-activated receptors (PPARa) have recently been shown to reduce the rewarding effects of nicotine in animals, but these drugs have not been approved for human use. The fibrates are a class of PPARa-activating medications that are widely prescribed to improve lipid profiles and prevent cardiovascular disease, but these drugs have not been tested in animal models of nicotine reward. Here, we examine the effects of clofibrate, a representative of the fibrate class, on reward-related behavioral, electrophysiological, and neurochemical effects of nicotine in rats and squirrel monkeys. Clofibrate prevented the acquisition of nicotine-taking behavior in naive animals, substantially decreased nicotine taking in experienced animals, and counteracted the relapse-inducing effects of re-exposure to nicotine or nicotine-associated cues after a period of abstinence. In the central nervous system, clofibrate blocked nicotine's effects on neuronal firing in the ventral tegmental area and on dopamine release in the nucleus accumbens shell. All of these results suggest that fibrate medications might promote smoking cessation. The fact that fibrates are already approved for human use could expedite clinical trials and subsequent implementation of fibrates as a treatment for tobacco dependence, especially in smokers with abnormal lipid profiles.

Hub and switches: endocannabinoid signalling in midbrain dopamine neurons

“…This scenario would provide a plausible cellular mechanism for the lack of effect of nicotine in increasing extracellular DA levels in the shell of the NAcc following URB597 treatment [40]. Accordingly, synthetic PPARa ligands, such as lipid lowering fibrates, prevent nicotine-induced excitation of DA cells and increases of extracellular DA levels in the NAcc shell [73]. Given that prolonged nicotine exposure upregulates nAChRs within the VTA [113 -115], PPARa negative modulation of b2*-nAChRs by fibrates, medications currently available to improve lipid profiles and prevent cardiovascular disease [116], might represent a promising therapeutical avenue to treat nicotine addiction.…”

“…Additionally, preclinical studies strongly suggest that PPARa could be an effective target for antismoking medication [39,[41][42][43]73,111,112]. Noteworthy, being PPARa-mediated actions directed at controlling either function and/or number of b2*-nAChRs, their effects are restricted to nicotine.…”

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

“…Many of the positive effects exhibited by the FAAH inhibitor URB597 in animal models of nicotine reward and reward-related neurochemical and electrophysiological effects have also been demonstrated with selective PPAR-α agonists that have no activity at CB 1 receptors Melis et al, 2013;Panlilio et al, 2012). However, selective enhancement of endogenous levels of the CB 1 agonist anandamide can block the reinstatement of nicotine seeking in rats, and both PPAR-α and CB 1 receptors contribute to the ability of URB597 to block the effects of nicotine on neuronal signaling (Luchicchi et al, 2010;Melis et al, 2008).…”

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Pioglitazone and ciglitazone, which is another thiazolidinedione selective for PPARγ, blocked the expression of locomotor sensitization to MA in mice (Maeda et al, 2007). Additionally, in rodents and nonhuman primates, clofibrate, a fibrate medication and selective PPARα agonist, blocked nicotineinduced VTA firing and DA release in the NAcc at the molecular level, and at the behavioral level it blocked the acquisition of nicotine-seeking behavior in nondependent animals, decreased nicotine self-administration in dependent animals, and prevented relapse to nicotine seeking in abstinent animals (Panlilio et al, 2012). Thus, in rodents and nonhuman primates, PPAR agonists may be effective in reducing the motivational and salient properties of multiple drugs (i.e., MA, alcohol, and nicotine) by modulating neurotransmission within the common reward pathway by which drugs of abuse are thought to exert their positively reinforcing effects.…”