Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice: Involvement of allopregnanolone biosynthesis

Palmitoylethanolamde (PEA) is an endogenous lipid neuromodulator that mediates a broad spectrum of pharmacological effects by activation of peroxisome proliferator-activated receptor alpha (PPAR-α). Detectable or high levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Here we report evidence that PEA, activating PPAR-α receptor and involving neurosteroids de novo synthesis, modulates pentobarbital-evoked hypnotic effect. A single i.c.v. administration of PEA (1–5 µg) increases pentobarbital induced loss of righting reflex (LORR) duration in mice. This effect is mimicked by GW7647 (3 µg), a synthetic PPAR-α agonist, and disappears in PPAR-α knockout mice.Antagonism experiments strongly support the engaging of neurosteroidogenic pathway in the increase of LORR duration induced by PEA. This effect disappeared using two inhibitors blocking the key steps of neurosteroids synthesis, aminogluthetimide and finasteride. Moreover, we demonstrated that in brainstem PEA increased the expression of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc), both involved in neurosteroidogenesis. Accordingly, allopregnanolone (ALLO) levels were in turn higher in brainstem of PEA and pentobarbital treated mice vs pentobarbital alone, as revealed by quantitative analysis using gas chromatography-mass spectrometry.A Our results demonstrate that exogenous administration of PEA, through a PPAR-α-dependent mechanism, modulates neurosteroids formation increasing ALLO levels and leading to a positive modulation of GABAA receptor. These data further strengthen our previous data on the role of PPAR-α in PEA's actions and could provide a new framework to understand its role in the CNS.