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This article is the author's final published version in International Journal of Molecular Sciences, Volume 22, Issue 10, 2 May 2021, Article number 5160.

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Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

his article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (


Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX1 and OX2, Gq-coupled GPCRs. We examined the effect of a selective OX1 agonist, OXA (17-33) on cytosolic calcium concentration, [Ca2+ ]i, in neurons of nucleus accumbens, an important area in the reward circuit. OXA (17-33) increased [Ca2+ ]i in a dose-dependent manner; the effect was prevented by SB-334867, a selective OX1 receptors antagonist. In Ca2+-free saline, the OXA (17-33)-induced increase in [Ca2+ ]i was not affected by pretreatment with bafilomycin A1, an endo-lysosomal calcium disrupter, but was blocked by 2-APB and xestospongin C, antagonists of inositol-1,4,5-trisphosphate (IP3 ) receptors. Pretreatment with VU0155056, PLD inhibitor, or BD-1047 and NE-100, Sigma-1R antagonists, reduced the [Ca2+ ]i response elicited by OXA (17-33). Cocaine potentiated the increase in [Ca2+ ]i by OXA (17-33); the potentiation was abolished by Sigma-1R antagonists. Our results support an additional signaling mechanism for orexin A-OX1 via choline-Sigma-1R and a critical role for Sigma-1R in the cocaine–orexin A interaction in nucleus accumbens neurons.

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