Physiological Role of Peroxisome Proliferator-Activated Receptors Type Alpha on Dopamine Systems

The discovery that N-acylethanolamines, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), acting as endogenous ligands of alpha-type peroxisome proliferator-activated receptors (PPAR alpha), block nicotine-induced excitation of dopamine neurons revealed their role as important endogenous negative modulators of nicotinic receptors containing beta 2 subunits (denoted beta 2*-nAChRs) on dopamine neurons, which are key to the brain reward system. Using mass-spectrometry data analysis from rodent brain slices containing the midbrain, we characterized the effects induced by modulation of PPAR alpha on PEA and OEA levels. PEA and OEA constitutive levels in the midbrain are higher than endocannabinoids (e. g. anandamide, 2-arachidonoylglycerol), and depend upon excessive input drive and the metabolic state of the cells. Accordingly, OEA and PEA synthesis is affected when adding low concentrations of fatty acids (endogenous PPAR alpha ligands), most likely through activation of PPAR alpha. Indeed, PPAR alpha activation increases PEA and OEA levels, which may further sustain PPAR activity. Given this, it is likely that these molecules dynamically affect dopamine function and excitability, as well as their dependent behaviour. Consequently, N-acylethanolamines may confer less vulnerability towards disruption of dynamic balance of dopamine-acetylcholine systems through PPAR alpha activation. Finally, using pharmacological and/or nutritional strategies which target PPAR alpha might represent a promising therapeutic approach to prevent disorders often related to neuro-inflammation, stress and abnormal beta 2*-nAChR function.