Orexin-A up-regulates dopamine D2 receptor and mRNA in the nucleus accumbens Shell
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ORIGINAL ARTICLE
Orexin‑A up‑regulates dopamine D2 receptor and mRNA in the nucleus accumbens Shell Sandra Morales‑Mulia1 · Víctor Manuel Magdaleno‑Madrigal2 · Humberto Nicolini3 · Alma Genis‑Mendoza3,4 · Marcela Morales‑Mulia5 Received: 6 April 2020 / Accepted: 3 November 2020 © Springer Nature B.V. 2020
Abstract Orexins-A (OrxA) and -B (OrxB) neuropeptides are synthesized by a group of neurons located in the lateral hypothalamus and adjacent perifornical area, which send their projections to the mesolimbic dopaminergic (DAergic) system including ventral tegmental area and nucleus accumbens (NAc), where orexin receptors are expressed. NAc plays a central role in reward-seeking behavior and drug abuse. NAc-neurons express dopamine-1 (D1R) and dopamine-2 (D2R) receptors. Orexins bind to their two cognate G-protein-coupled receptors, orexin-receptor type-1 ( Orx1R) and type-2 ( Orx2R). Orexin receptor signaling is involved in behaviors such as motivation and addiction. Orexin-containing neurons modulate DAergic activity that is key in synaptic plasticity induced by addictive drugs. However, the effect of OrxA on expression and content of DAergic receptors in NAc is unknown. The purpose of this study was to investigate whether OrxA can alter gene expression and protein levels of D1R/D2R in NAc. Gene expression was evaluated by real-time PCR analysis and protein levels by western blot in rats. The results show that intracerebroventricular (i.c.v.) injection of OrxA increases both gene transcription and protein content of D2R but fails to modify D1R. This effect was also confirmed with OrxA infusion in NAc/Shell. Our results demonstrate for the first time that OrxA induces up-regulation of gene and protein of D2R in NAc. These findings support the hypothesis that OrxA modulates the DAergic transmission and this may serve to understand how orexin signaling enhances DA responses at baseline conditions and in response to psychostimulants. Keywords Orexin system · Dopamine receptors · Mesolimbic system · Nucleus accumbens
Introduction
* Marcela Morales‑Mulia [email protected] 1
Departamento de Biología Celular, Facultad de Ciencias, UNAM, Mexico, DF, Mexico
2
Neurofisiología del Control y la Regulación, Dirección de Neurociencias, INPRFM, Mexico, DF, Mexico
3
Laboratory of Genomics of Psychiatric Diseases, Neurodegenerative and Addictions, National Institute of Genomic Medicine, Mexico, Mexico
4
Hospital Psiquiátrico Infantil “Dr. Juan N. Navarro” Psychiatric Attention Services, Mexico, Mexico
5
Bases Moleculares de las Adicciones, Subdirección de Investigaciones Clínicas, INPRFM, Calzada México‑Xochimilco 101, San Lorenzo Huipulco, Tlalpan, 14370 Mexico, DF, Mexico
Orexin signaling has been identified as a critical element of mesolimbic DAergic system, a brain circuit implicated in motivation- and addiction-related behaviors [1–3]. The orexins are synthesized by a group of neurons located in the lateral (LH) and perifornical area (PFA) [4, 5]. Orexin-A (OrxA or hypocretin-1) and orexin
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