Mechanisms of N-oleoyldopamine activation of central histaminergic neurons. (December 2018) - De Luca, Roberto
Abstract: Histaminergic (HA) neurons located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus fire exclusively during waking and support many physiological functions. We investigated the role of the endovanilloid N -oleoyldopamine (OLDA) in TMN, where dopamine synthesis and its conjugation with oleic acid likely occur. We show that several known targets of OLDA including TRPV1 and cannabinoid receptors are expressed in HA neurons. In contrast to capsaicin, which failed to increase firing of HA neurons in TRPV1 knockout mice (TRPVI KO), OLDA was still able to induce excitation. This excitation was not sensitive to the blockade of cannabinoid receptors 1 and 2 and could result from OLDA interaction with GPR119, as the ligand of GPR119, oleoylethanolamide (OEA), also increased the firing of HA neurons. However, we ruled out this possibility as OEA- (but not OLDA-) excitation was abolished by the PPAR (peroxisome proliferator activated receptor) alpha antagonist MK886. The dopamine uptake blocker nomifensine blanked OLDA-excitation and dopamine receptor antagonists abolished the OLDA action in TRPV1 KO mice. Therefore OLDA excites HA neurons through multiple targets suggesting a central role of the histaminergic system in the behavioral stimulation seen after systemic OLDA application. Graphical abstract: Highlights: OLDA is an endogenous conjugate of dopamine and oleic acid. OLDA is an endovanilloid that excites histaminergic neurons through TRPV1. OLDA-excitation in TRPV1 KO mice is prevented by dopamine receptor antagonists. Expression of further multiple targets of OLDA is evident in histamine neurons. OLDA-excitation is independent of cannabinoid receptors despite excitatory action of their respective agonists.