Stimulation of Peroxisome Proliferator-Activated Receptor-α by N-Palmitoylethanolamine Engages Allopregnanolone Biosynthesis to Modulate Emotional Behavior

BACKGROUND: The endocannabinoid and neurosteroid systems regulate emotions and stress responses. Activation of peroxisome proliferator-activated receptor (PPAR)-alpha by the endocannabinoid congener N-palmitoylethanolamine (PEA) regulates pathophysiological systems (e.g., inflammation, oxidative stress) and induces peripheral biosynthesis of allopregnanolone, a gamma-aminobutyric acidergic neurosteroid implicated in mood disorders. However, effects of PPAR-alpha on emotional behavior are poorly understood. METHODS: We studied the impact of PPAR-alpha activation on emotional behavior in a mouse model of posttraumatic stress disorder. Neurosteroid levels before and after PEA treatment were measured by gas chromatography-mass spectrometry in relevant brain regions of socially isolated versus group-housed mice exposed to the contextual fear conditioning test, elevated plus maze test, forced swim test, and tail suspension test. Neurosteroidogenic enzyme levels were quantified in hippocampus by Western blot. RESULTS: PEA administered in a model of conditioned contextual fear reconsolidation blockade facilitated fear extinction and fear extinction retention and induced marked antidepressive- and anxiolytic-like effects in socially isolated mice with reduced brain allopregnanolone levels. These effects were mimicked by the PPAR-alpha synthetic agonists, fenofibrate and GW7647, and were prevented by PPAR-alpha deletion, PPAR-alpha antagonists, and neurosteroid-enzyme inhibitors. Behavioral improvements correlated with PEA-induced upregulation of PPAR-alpha, neurosteroidogenic enzyme expression, and normalization of corticolimbic allopregnanolone levels. CONCLUSIONS: This evidence supports a previously unknown role for PPAR-alpha in behavior regulation and suggests new strategies for the treatment of neuropsychopathologies characterized by deficient neurosteroidogenesis, including posttraumatic stress disorder and major depressive disorder.