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

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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.HIGHLIGHTSN-oleoyldopamine (OLDA) is synthesized in catecholaminergic neurons.OLDA excites mesencephalic dopaminergic neurons through TRPV1.Inhibition by OLDA in TRPV1KO mice is similar to that by the dopamine uptake inhibitor nomifensine.OLDA interacts with the cannabinoid system.OLDA-like molecules offer new strategies for the treatment of movement disorders.

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