N-oleoyldopamine modulates activity of midbrain dopaminergic neurons through multiple mechanisms

Neuropharmacology. 2017 Jun;119:111-122. doi: 10.1016/j.neuropharm.2017.04.011. Epub 2017 Apr 9.

Abstract

N-oleoyl-dopamine (OLDA) is an amide of dopamine and oleic acid, synthesized in catecholaminergic neurons. The present study investigates OLDA targets in midbrain dopaminergic (DA) neurons. Substantia Nigra compacta (SNc) DA neurons recorded in brain slices were excited by OLDA in wild type mice. In transient receptor potential vanilloid 1 (TRPV1) knockout (KO) mice, however, SNc DA neurons displayed sustained inhibition of firing. In the presence of the dopamine type 2 receptor (D2R) antagonist sulpiride or the dopamine transporter blocker nomifensine no such inhibition was observed. Under sulpiride OLDA slightly excited SNc DA neurons, an action abolished upon combined application of the cannabinoid1 and 2 receptor antagonists AM251 and AM630. In ventral tegmental area (VTA) DA neurons from TRPV1 KO mice a transient inhibition of firing by OLDA was observed. Thus OLDA modulates the firing of nigrostriatal DA neurons through interactions with TRPV1, cannabinoid receptors and dopamine uptake. These findings suggest further development of OLDA-like tandem molecules for the treatment of movement disorders including Parkinson's disease.

Keywords: (-)-quinpirole hydrochloride (PubChem CID: 55397); (S)-(-)-sulpiride (PubChem CID: 688272); AM251 (PubChem CID: 2125); AM630 (PubChem CID: 4302963); AMG9810 (PubChem CID: 680502); Action potential current; CNQX disodium salt (PubChem CID: 6093155); D-AP5 (PubChem CID: 135342); Dopamine; Endocannabinoids; N-oleoyldopamine (PubChem CID: 5282106); Parkinson's disease; Patch-clamp; Substantia nigra; URB 597 (PubChem CID: 1383884); WIN55212,2 mesylate (PubChem CID: 6604176); gabazine (PubChem CID: 107895); nomifensine maleate (PubChem CID: 5358907).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / pharmacology
  • Action Potentials / drug effects
  • Age Factors
  • Animals
  • Animals, Newborn
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cannabinoid Receptor Antagonists / pharmacology
  • Dopamine / analogs & derivatives*
  • Dopamine / pharmacology
  • Dopamine Agents / pharmacology*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopaminergic Neurons / drug effects*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mesencephalon / cytology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neural Inhibition / drug effects
  • Patch-Clamp Techniques
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • 3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide
  • Acrylamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cannabinoid Receptor Antagonists
  • Dopamine Agents
  • Dopamine Plasma Membrane Transport Proteins
  • Luminescent Proteins
  • Piperidines
  • Pyrazoles
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • AM 251
  • Tyrosine 3-Monooxygenase
  • N-oleoyldopamine
  • Dopamine