Targeting the interaction between fatty acid ethanolamides and nicotinic receptors: therapeutic perspectives

Nicotine is one of the drugs of abuse that frequently causes addiction and relapse during abstinence. Nicotine's strong addicting properties reside in its ability to enhance dopamine transmission, and to induce specific changes in synaptic plasticity. Currently, approved therapies for smoking cessation increase the chances of remaining abstinent, but lack high levels of efficacy and are associated with significant adverse side effects. As a result, there is an urgent need for more effective antismoking medications. Studies have revealed that drugs targeting the peroxisome proliferator-activated-receptor-α (PPARα) show promise for the treatment of nicotine addiction. These drugs include synthetic PPARα ligands, such as the clinically available hypolipidemic fibrates, and drugs that increase levels of endogenous endocannabinoid-like fatty acid ethanolamides (FAEs) that act as PPARα agonists. In this review, we will discuss the specific interaction between PPARα and nicotine, and the molecular mechanisms whereby these intracellular receptors regulate nicotinic acetylcholine receptor functions in neurons. Modulation of neurophysiological, neurochemical and behavioral effects of nicotine by PPARα will be also reviewed. Indeed, a picture is emerging where FAEs are endogenous regulators of acetylcholine transmission. Notably, the implications of this specific cross talk extend beyond nicotine addiction, and might bear relevance for psychiatric disorders and epilepsy.