The discovery that N-acylethanolamines, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), acting as endogenous ligands of alpha-type peroxisome proliferator-activated receptors (PPARα), block nicotine-induced excitation of  dopamine neurons revealed their role as important endogenous negative modulators of nicotinic receptors containing β2 subunits (denoted β2*-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 PPARα on PEA and OEA levels. PEA and OEA constitutive levels in the midbrain are higher thanendocannabinoids (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 PPARα ligands), most likely through activation of PPARα. Indeed, PPARα activation increases PEA and OEA levels, which may further sustain PPARα 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 PPARα activation. Finally, using pharmacological and/or nutritional strategies which target PPARα might represent a promising therapeutic approach to prevent disorders often related to neuro-inflammation, stress  and  abnormal β2*-nAChR function.