{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T14:47:18Z","timestamp":1774882038799,"version":"3.50.1"},"reference-count":69,"publisher":"Society for Neuroscience","issue":"4","license":[{"start":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T00:00:00Z","timestamp":1627344000000},"content-version":"vor","delay-in-days":237,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"name":"NIMH IRP","award":["1ZIAMH002386"],"award-info":[{"award-number":["1ZIAMH002386"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2021,1,27]]},"abstract":"<jats:p>Elucidation of the mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor-expressing neurons leading to acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK\u2192Egr-1\/Zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons of NAc slices; and in either male or female mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the NAc in adult mice, using adeno-associated virus-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1\/Zif268 upregulation in D1-medium spiny neurons and cocaine-induced behaviors, including locomotor sensitization and conditioned place preference. Abrogation of NCS-Rapgef2 gene expression in mPFC and BLA, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium\/calmodulin-dependent kinase II\u03b1 promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1\/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1 receptor-expressing neurons in the NAc, but not in corticolimbic areas, contributes to cocaine-induced locomotor sensitization and conditioned place preference. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2\/phospho-ERK activation, independently of PKA\/CREB signaling.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>\n                    ERK phosphorylation in dopamine D1 receptor-expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioral adaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the NAc is required for activation of ERK and Egr-1\/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequent enhanced locomotor response and drug seeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-medium spiny neurons encode the experience of psychomotor stimulant exposure.\n                  <\/jats:p>","DOI":"10.1523\/jneurosci.1497-20.2020","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T17:51:53Z","timestamp":1606931513000},"page":"711-725","source":"Crossref","is-referenced-by-count":24,"title":["Cocaine-Dependent Acquisition of Locomotor Sensitization and Conditioned Place Preference Requires D1 Dopaminergic Signaling through a Cyclic AMP, NCS-Rapgef2, ERK, and Egr-1\/Zif268 Pathway"],"prefix":"10.1523","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0706-1581","authenticated-orcid":false,"given":"Sunny Zhihong","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Sweat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sam P.","family":"Dahlke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathleen","family":"Loane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3085-8801","authenticated-orcid":false,"given":"Gunner","family":"Drossel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8813-8183","authenticated-orcid":false,"given":"Wenqin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hugo A.","family":"Tejeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R.","family":"Gerfen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lee E.","family":"Eiden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"393","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"2023041803450189000_41.4.711.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.42.082701.145401"},{"key":"2023041803450189000_41.4.711.2","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2013.00152"},{"key":"2023041803450189000_41.4.711.3","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1039-08.2008"},{"key":"2023041803450189000_41.4.711.4","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1711-05.2005"},{"key":"2023041803450189000_41.4.711.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2013.02.026"},{"key":"2023041803450189000_41.4.711.6","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2013.00172"},{"key":"2023041803450189000_41.4.711.7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1521238113"},{"key":"2023041803450189000_41.4.711.8","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2013.00013"},{"key":"2023041803450189000_41.4.711.9","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-203042"},{"key":"2023041803450189000_41.4.711.10","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2003993"},{"key":"2023041803450189000_41.4.711.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.529321"},{"key":"2023041803450189000_41.4.711.12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.790329"},{"key":"2023041803450189000_41.4.711.13","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.6b00462"},{"key":"2023041803450189000_41.4.711.14","doi-asserted-by":"publisher","DOI":"10.1038\/376524a0"},{"key":"2023041803450189000_41.4.711.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.03.014"},{"key":"2023041803450189000_41.4.711.16","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301014"},{"key":"2023041803450189000_41.4.711.17","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-clinpsy-032210-104454"},{"key":"2023041803450189000_41.4.711.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.10.116"},{"key":"2023041803450189000_41.4.711.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0019415"},{"key":"2023041803450189000_41.4.711.20","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-12-05042.2002"},{"key":"2023041803450189000_41.4.711.21","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3952-07.2008"},{"key":"2023041803450189000_41.4.711.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.10.016"},{"key":"2023041803450189000_41.4.711.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2006.08.012"},{"key":"2023041803450189000_41.4.711.24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003445"},{"key":"2023041803450189000_41.4.711.25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0504657102"},{"key":"2023041803450189000_41.4.711.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.05.011"},{"key":"2023041803450189000_41.4.711.27","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0473-17.2017"},{"key":"2023041803450189000_41.4.711.28","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0248-17.2017"},{"key":"2023041803450189000_41.4.711.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.11.006"},{"key":"2023041803450189000_41.4.711.30","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3100"},{"key":"2023041803450189000_41.4.711.31","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1706-04.2004"},{"key":"2023041803450189000_41.4.711.32","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00972-8"},{"key":"2023041803450189000_41.4.711.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511244103"},{"key":"2023041803450189000_41.4.711.34","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2015.75"},{"key":"2023041803450189000_41.4.711.35","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2011.00041"},{"key":"2023041803450189000_41.4.711.36","doi-asserted-by":"publisher","DOI":"10.1126\/science.1188472"},{"key":"2023041803450189000_41.4.711.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2006.10.005"},{"key":"2023041803450189000_41.4.711.38","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-018-0370-y"},{"key":"2023041803450189000_41.4.711.39","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00716-X"},{"key":"2023041803450189000_41.4.711.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.08.006"},{"key":"2023041803450189000_41.4.711.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2016.07.003"},{"key":"2023041803450189000_41.4.711.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.12.019"},{"key":"2023041803450189000_41.4.711.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2015.12.039"},{"key":"2023041803450189000_41.4.711.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.01.016"},{"key":"2023041803450189000_41.4.711.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.07.001"},{"key":"2023041803450189000_41.4.711.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2010.08.031"},{"key":"2023041803450189000_41.4.711.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2014.04.005"},{"key":"2023041803450189000_41.4.711.48","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.044792"},{"key":"2023041803450189000_41.4.711.49","doi-asserted-by":"publisher","DOI":"10.1901\/jeab.2005.105-04"},{"key":"2023041803450189000_41.4.711.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2010.03.034"},{"key":"2023041803450189000_41.4.711.51","doi-asserted-by":"publisher","DOI":"10.1080\/09652140050111681"},{"key":"2023041803450189000_41.4.711.52","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3381"},{"key":"2023041803450189000_41.4.711.53","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.388413"},{"key":"2023041803450189000_41.4.711.54","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0852-07.2007"},{"key":"2023041803450189000_41.4.711.55","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.68.1.821"},{"key":"2023041803450189000_41.4.711.56","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5492-07.2008"},{"key":"2023041803450189000_41.4.711.57","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1038\/s41380-019-0484-3","article-title":"Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion","volume":"25","author":"Soares-Cunha","year":"2020","journal-title":"Mol Psychiatry"},{"key":"2023041803450189000_41.4.711.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2007.07.051"},{"key":"2023041803450189000_41.4.711.59","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.44.101802.121415"},{"key":"2023041803450189000_41.4.711.60","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.12.005"},{"key":"2023041803450189000_41.4.711.61","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/nyas.13989","article-title":"The neurobiology of addiction","volume":"1451","author":"Uhl","year":"2019","journal-title":"Ann NY Acad Sci"},{"key":"2023041803450189000_41.4.711.62","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-23-08701.2000"},{"key":"2023041803450189000_41.4.711.63","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408305102"},{"key":"2023041803450189000_41.4.711.64","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-7-20"},{"key":"2023041803450189000_41.4.711.65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511030103"},{"key":"2023041803450189000_41.4.711.66","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4601-05.2006"},{"key":"2023041803450189000_41.4.711.67","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2009.143"},{"key":"2023041803450189000_41.4.711.68","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90026-4"},{"key":"2023041803450189000_41.4.711.69","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1013543107"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.1497-20.2020","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.1497-20.2020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T08:23:56Z","timestamp":1681806236000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.1497-20.2020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,2]]},"references-count":69,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,1,27]]},"published-print":{"date-parts":[[2021,1,27]]}},"alternative-id":["10.1523\/JNEUROSCI.1497-20.2020"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.1497-20.2020","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.07.02.184754","asserted-by":"object"}]},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,2]]}}}