2. Academic Validation
  3. Mechanisms of N-oleoyldopamine activation of central histaminergic neurons

Mechanisms of N-oleoyldopamine activation of central histaminergic neurons

  • Neuropharmacology. 2018 Dec:143:327-338. doi: 10.1016/j.neuropharm.2018.09.006.
Roberto De Luca 1,  Karolina Mazur 2,  Anna Kernder 1,  Tatsiana Suvorava 3,  Georg Kojda 3,  Helmut L Haas 1,  Olga A Sergeeva 4
Affiliations

Affiliations

  • 1 Institute of Neural and Sensory Physiology, Medical Faculty of Heinrich-Heine-University (HHU), D-40225, Düsseldorf, Germany.
  • 2 Institute of Clinical Neurosciences and Medical Psychology, Medical Faculty, HHU, D-40225, Düsseldorf, Germany.
  • 3 Institute of Pharmacology and Clinical Pharmacology, Medical Faculty, HHU, D-40225, Düsseldorf, Germany.
  • 4 Institute of Neural and Sensory Physiology, Medical Faculty of Heinrich-Heine-University (HHU), D-40225, Düsseldorf, Germany; Institute of Clinical Neurosciences and Medical Psychology, Medical Faculty, HHU, D-40225, Düsseldorf, Germany. Electronic address: [email protected].
PMID: 30219501 DOI: 10.1016/j.neuropharm.2018.09.006
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.

Keywords

(S)-(−)-sulpiride (688272); AM251 (2125); AM630 (4302963); Action potential current; CNQX (3721046); Cannabinoid receptor; Capsaicin (1548943) and MK886 (4519262); D-AP5 (13532); Dopamine; Dopamine transporter; JWH 133 (6918505); MPEP (3025961); Mouse brain slices; N-oleoyldopamine (5282106); Patch-clamp; R-alpha-methylhistamine (156615); URB 597 (1383884) and WIN55212,2 mesylate (6604176); gabazine (107896) and SCH23390 (6440792); nomifensine maleate (5358907); oleoylethanolamide (5283454); probenecid (4911); tetrodotoxin (11174599); thioperamide (3035905).

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