Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniquesin vivoandin vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-α (PPAR-α), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-α triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-α in the brain and provide a potential new target for the treatment of nicotine addiction.

Peroxisome proliferator-activated receptors (PPARs) have long been known as mediators of several physiological functions, among which the best characterized are lipid metabolism, energy balance and anti-inflammation. Their rather large and promiscuous ligand binding site has been recently discovered to accommodate, among a plethora of lipid molecules and metabolic intermediates, endocannabinoids and their cognate compounds, specifically belonging to the Nacylethanolamine group. In fact, oleoylethanolamide, palmitoylethanolamide and probably anandamide bind with relatively high affinity to PPARs and have now been included among their endogenous ligands. Through activation of PPARs these molecules exert a variety of physiological processes. Particularly, both long-term effects via genomic mechanisms and rapid non-genomic actions have been described, which in several instances are opposite to those evoked by activation of “classical” surface cannabinoid receptors. In this review, we describe how these effects are relevant under diverse physiological and pathophysiological circumstances, such as lipid metabolism and feeding behaviour, neuroprotection and epilepsy, circadian rhythms, addiction and cognition. A picture is emerging where nuclear receptors are involved in anorexiant, anti-inflammatory, neuroprotective, anti-epileptic, wakefulness- and cognitive-enhancing, and anti-addicting properties of endocannabinoid-like molecules. Further studies are necessary to fully understand cellular mechanisms underlying the interactions between endocannabinoids and PPARs, but also between their surface and nuclear receptors, and to exploit their potential therapeutic applications.