{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:00:02Z","timestamp":1760234402805,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30DA013429"],"award-info":[{"award-number":["P30DA013429"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2013orexin A interaction in nucleus accumbens neurons.<\/jats:p>","DOI":"10.3390\/ijms22105160","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T11:10:06Z","timestamp":1620904206000},"page":"5160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Choline-Sigma-1R as an Additional Mechanism for Potentiation of Orexin by Cocaine"],"prefix":"10.3390","volume":"22","author":[{"given":"Jeffrey L.","family":"Barr","sequence":"first","affiliation":[{"name":"Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pingwei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. Cristina","family":"Brailoiu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugen","family":"Brailoiu","sequence":"additional","affiliation":[{"name":"Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0092-8674(00)80949-6","article-title":"Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior","volume":"92","author":"Sakurai","year":"1998","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1073\/pnas.95.1.322","article-title":"The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity","volume":"95","author":"Kilduff","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/B978-0-444-59489-1.00007-0","article-title":"Multiple roles for orexin\/hypocretin in addiction","volume":"198","author":"Mahler","year":"2012","journal-title":"Prog. Brain Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/bs.pbr.2017.08.005","article-title":"Functional roles of orexin\/hypocretin receptors in reward circuit","volume":"235","author":"Haghparast","year":"2017","journal-title":"Prog. Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1124\/pr.57.2.5","article-title":"International Union of Pharmacology. XLVI. G protein-coupled receptor list","volume":"57","author":"Foord","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.bbrc.2016.05.130","article-title":"G-protein-dependency of orexin\/hypocretin receptor signalling in recombinant Chinese hamster ovary cells","volume":"476","author":"Kukkonen","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108013","DOI":"10.1016\/j.neuropharm.2020.108013","article-title":"Recent perspectives on orexin\/hypocretin promotion of addiction-related behaviors","volume":"168","author":"Hopf","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.biochi.2013.06.015","article-title":"Lipid signaling cascades of orexin\/hypocretin receptors","volume":"96","author":"Kukkonen","year":"2014","journal-title":"Biochimie"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1007\/s00018-008-8206-z","article-title":"Multiple phospholipase activation by OX(1) orexin\/hypocretin receptors","volume":"65","author":"Johansson","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1111\/j.1476-5381.2011.01565.x","article-title":"OX1 orexin\/hypocretin receptor activation of phospholipase D","volume":"165","author":"Jantti","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1749-6632.2000.tb06538.x","article-title":"Phospholipase D","volume":"905","author":"Exton","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.celrep.2018.12.051","article-title":"Choline is an intracellular messenger linking extracellular stimuli to IP3-evoked Ca(2+) signals through Sigma-1 receptors","volume":"26","author":"Brailoiu","year":"2019","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1016\/j.cell.2007.08.036","article-title":"Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival","volume":"131","author":"Hayashi","year":"2007","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.molbrainres.2005.02.002","article-title":"Opposite effects of sleep rebound on orexin OX1 and OX2 receptor expression in rat brain","volume":"136","author":"Hipolide","year":"2005","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"88","DOI":"10.3389\/fnins.2019.00088","article-title":"Nucleus accumbens shell Orexin-1 receptors are critical mediators of binge intake in excessive-drinking individuals","volume":"13","author":"Lei","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"145922","DOI":"10.1016\/j.brainres.2018.08.025","article-title":"Therapeutics development for addiction: Orexin-1 receptor antagonists","volume":"1731","author":"Perrey","year":"2020","journal-title":"Brain Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1007\/s12264-019-00447-9","article-title":"Orexin receptor antagonists as emerging treatments for psychiatric disorders","volume":"36","author":"Han","year":"2020","journal-title":"Neurosci. Bull."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/s40263-014-0179-x","article-title":"Orexin\/hypocretin based pharmacotherapies for the treatment of addiction: DORA or SORA?","volume":"28","author":"Khoo","year":"2014","journal-title":"CNS Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1111\/ejn.12866","article-title":"Orexin-1 receptor signaling increases motivation for cocaine-associated cues","volume":"41","author":"Bentzley","year":"2015","journal-title":"Eur. J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1124\/jpet.111.187567","article-title":"Orexin-1 receptor mediation of cocaine seeking in male and female rats","volume":"340","author":"Zhou","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1021\/cn500246j","article-title":"Hypocretin\/Orexin regulation of dopamine signaling and cocaine self-administration is mediated predominantly by hypocretin receptor 1","volume":"6","author":"Prince","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112365","DOI":"10.1016\/j.bbr.2019.112365","article-title":"The role of the nucleus accumbens OXR1 in cocaine-induced locomotor sensitization","volume":"379","author":"Yang","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1097\/WNR.0000000000000120","article-title":"Blockade of hypocretin receptor-1 preferentially prevents cocaine seeking: Comparison with natural reward seeking","volume":"25","author":"Weiss","year":"2014","journal-title":"Neuroreport"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/379606a0","article-title":"Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter","volume":"379","author":"Giros","year":"1996","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/npp.2009.110","article-title":"Neurocircuitry of addiction","volume":"35","author":"Koob","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0014-2999(88)90058-1","article-title":"Cocaine binding at sigma receptors","volume":"149","author":"Sharkey","year":"1988","journal-title":"Eur. J. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1523\/JNEUROSCI.06-06-01757.1986","article-title":"Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)3H-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine","volume":"6","author":"Gundlach","year":"1986","journal-title":"J. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0306-4522(00)00014-2","article-title":"Immunocytochemical localization of the sigma(1) receptor in the adult rat central nervous system","volume":"97","author":"Alonso","year":"2000","journal-title":"Neuroscience"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.ceca.2015.05.001","article-title":"Mechanisms of activation of nucleus accumbens neurons by cocaine via sigma-1 receptor-inositol 1,4,5-trisphosphate-transient receptor potential canonical channel pathways","volume":"58","author":"Barr","year":"2015","journal-title":"Cell Calcium"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Feng, X.M., Mi, W.L., Xia, F., Mao-Ying, W.L., Jiang, J.W., Xiao, S., Wang, Z.F., Wang, Y.Q., and Wu, G.C. (2012). Involvement of spinal orexin A in the electroacupuncture analgesia in a rat model of post-laparotomy pain. BMC Complement. Altern. Med., 12.","DOI":"10.1186\/1472-6882-12-225"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1038\/sj.bjp.0703953","article-title":"SB-334867-A: The first selective orexin-1 receptor antagonist","volume":"132","author":"Smart","year":"2001","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1093\/oxfordjournals.jbchem.a021780","article-title":"2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release","volume":"122","author":"Maruyama","year":"1997","journal-title":"J. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7972","DOI":"10.1073\/pnas.85.21.7972","article-title":"Bafilomycins: A class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells","volume":"85","author":"Bowman","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1038\/nchembio.140","article-title":"Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness","volume":"5","author":"Scott","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/0014-2999(95)00208-3","article-title":"Characterization of two novel sigma receptor ligands: Antidystonic effects in rats suggest sigma receptor antagonism","volume":"280","author":"Matsumoto","year":"1995","journal-title":"Eur. J. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/0024-3205(96)00458-4","article-title":"Solubilization and characterization of binding sites for [3H]NE-100, a novel and potent sigma 1 ligand, from guinea pig brain","volume":"59","author":"Chaki","year":"1996","journal-title":"Life Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bjornstrom, K., Turina, D., Strid, T., Sundqvist, T., and Eintrei, C. (2014). Orexin A inhibits propofol-induced neurite retraction by a phospholipase D\/protein kinase Cepsilon-dependent mechanism in neurons. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0097129"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1152\/physrev.00006.2016","article-title":"The Inositol Trisphosphate\/Calcium signaling pathway in health and disease","volume":"96","author":"Berridge","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1083\/jcb.201506022","article-title":"Sigma1 receptors inhibit store-operated Ca2+ entry by attenuating coupling of STIM1 to Orai1","volume":"213","author":"Srivats","year":"2016","journal-title":"J. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.pharmthera.2009.07.001","article-title":"The pharmacology of sigma-1 receptors","volume":"124","author":"Maurice","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"880","DOI":"10.3390\/ph4060880","article-title":"A role for sigma receptors in stimulant self-administration and addiction","volume":"4","author":"Katz","year":"2011","journal-title":"Pharmaceuticals"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1517\/14728222.2011.560837","article-title":"Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders","volume":"15","author":"Hayashi","year":"2011","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/npp.2017.158","article-title":"Effects of suvorexant, a dual Orexin\/Hypocretin receptor antagonist, on impulsive behavior associated with cocaine","volume":"43","author":"Gentile","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5320","DOI":"10.1021\/jm100541c","article-title":"Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia","volume":"53","author":"Cox","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.drugalcdep.2017.04.015","article-title":"HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens","volume":"178","author":"Brailoiu","year":"2017","journal-title":"Drug Alcohol Depend."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1016\/S0021-9258(19)83641-4","article-title":"A new generation of Ca2+ indicators with greatly improved fluorescence properties","volume":"260","author":"Grynkiewicz","year":"1985","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5160\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:00:16Z","timestamp":1760162416000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/10\/5160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,13]]},"references-count":46,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["ijms22105160"],"URL":"https:\/\/doi.org\/10.3390\/ijms22105160","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,5,13]]}}}