Choline-Sigma-1R as an Additional Mechanism for Potentiation of Orexin by Cocaine
Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX<sub>1</sub> and OX<sub>2</sub>, Gq-coupled GPCRs. We examined the effect of a selective OX<sub>1</sub> agonist, OXA (17-33) on cytosolic calc...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/10/5160 |
| Summary: | Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX<sub>1</sub> and OX<sub>2</sub>, Gq-coupled GPCRs. We examined the effect of a selective OX<sub>1</sub> agonist, OXA (17-33) on cytosolic calcium concentration, [Ca<sup>2+</sup>]<sub>i</sub>, in neurons of nucleus accumbens, an important area in the reward circuit. OXA (17-33) increased [Ca<sup>2+</sup>]<sub>i</sub> in a dose-dependent manner; the effect was prevented by SB-334867, a selective OX<sub>1</sub> receptors antagonist. In Ca<sup>2+</sup>-free saline, the OXA (17-33)-induced increase in [Ca<sup>2+</sup>]<sub>i</sub> 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 (IP<sub>3</sub>) receptors. Pretreatment with VU0155056, PLD inhibitor, or BD-1047 and NE-100, Sigma-1R antagonists, reduced the [Ca<sup>2+</sup>]<sub>i</sub> response elicited by OXA (17-33). Cocaine potentiated the increase in [Ca<sup>2+</sup>]<sub>i</sub> by OXA (17-33); the potentiation was abolished by Sigma-1R antagonists. Our results support an additional signaling mechanism for orexin A-OX<sub>1</sub> 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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| ISSN: | 1661-6596 1422-0067 |