THE ANOREXIANT EFFECT OF OLEOYLETHANOLAMIDE IS MODULATED BY NEURONAL HISTAMINE

The modulatory effect of both brain histamine (HA) and Oleoylethanolamide (OEA) on feeding behaviour is robust, but nothing is known about the temporal or causal relationship between HA and OEA in controlling food intake. To learn if OEA affects feeding behaviour via the histaminergic system we measured food consumption in normal and genetically or pharmacologically HA-deprived mice. We use sv129 WT and HDC-KO and CD1 male mice that were food deprived for 12 h and then received pharmacological treatments. Food consumption was measured every 15 min for the 1st h and at increasing intervals for the following 24 h. OEA-treated (10 mg/kg i.p. n = 16) WT mice ate significantly less than vehicle-treated WT mice (n = 16). However, the anorexiant effect of OEA was attenuated in HDC-KO mice (n = 28). OEA anorexiant effect was also attenuated in HA depleted CD1 (5 lg afluoromethyl- histidine i.c.v. n = 20), but not in control mice (n = 20). Treatment with the H3R antagonist ABT239 (3 mg/Kg i.p.) potentiated the effect of OEA (5 mg/kg, i.p. n = 20/treatment). In order to investigate if changes in neuronal activation are related with the behavioral differences, we evaluated the c-Fos expression in HDC-KO and WT (n = 3–5/treatment) mice using immunohistochemistry in brain areas involved in feeding behavior: Infralimbic Cortex (IL-Cx), Nucleus Accumbens (Nac) and Paraventricular Nucleus (PVN). Mice fasted for 12 h were treated with OEA (10 mg/kg i.p.) or vehicle and sacrificed after 2 hs. OEA treatment decreased the number of c-Fos+ cell nuclei in the Nac of both HDC-KO and WT mice. No changes were observed in the IL-Cx of either genotype. However, in the PVN an increase of c-Fos expression was observed in OEA-treated WT but not in HDC-KO mice. Our results indicate that the histaminergic system is involved in the anorexiant effects of OEA and that disregulation of PVN neuronal activity may be responsible for the partial lack of OEA efficacy in HA deficient mice.