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IEG induction after psychostimulant administration has been attributed to both PKA\u2010 and RapGEF2\u2010dependent signaling pathways initiated by D1 receptor stimulation by dopamine. However, it is not clear how each pathway contributes individually to IEG induction, dopaminoceptive neuronal activity, and neuronal plasticity. We used Cre\u2010LoxP technology and a novel Cre\u2010amplifier transgene to delete RapGEF2 only in D1\u2010MSNs, and investigate its role in cocaine\u2010induced IEG and behavioral responses. D1\u2010MSN\u2010specific RapGEF2 deletion blocked cocaine\u2010induced ERK phosphorylation and Egr\u20101 induction, without affecting cocaine self\u2010administration or c\u2010Fos induction by cocaine. Deletion of Rap1 in D1\u2010MSNs blocked cocaine\u2010induced p\u2010ERK and Egr\u20101 expression, but not the induction of c\u2010Fos. Like RapGEF2 deletion, Rap1 deletion from D1\u2010MSNs had no effect on final maintenance of stable cocaine self\u2010administration, although the rate of acquisition was significantly impaired. These results suggest that D1\u2010dependent activation of Egr1 is not ultimately required for cocaine self\u2010administration, although it may affect the behavioral dynamics of this process. Suppressing cAMP elevation in D1\u2010MSNs by D1\u2010specific expression of PDE4D3\u2010cat greatly reduced induction of both Egr\u20101 and c\u2010Fos in NAc after cocaine administration, demonstrating that induction of both IEGs requires cAMP elevation in D1\u2010MSNs. Specific inhibition of PKA activity via PKI\u2010alpha expression in D1\u2010MSNs also blocked both c\u2010Fos and Egr\u20101 induction. Thus, acute or chronic cocaine administration activates at least two separate cAMP effectors in D1\u2010MSNs. PKA activation leads to c\u2010Fos induction, likely through CREB, and to Egr1 activation via Rap1, likely through a previously reported dependence on RasGRP2. RapGEF2 activation leads exclusively to Egr1 induction. The finding that PKA activates the ERK\u2010Egr\u20101 signaling pathway by convergence on Rap1, and concomitantly activates c\u2010Fos independently of Rap1, may underlie selective effects of RapGEF2 and PKA inhibition on psychostimulant\u2010dependent behaviors in mice.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc70374-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.70374","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T05:15:56Z","timestamp":1774847756000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cocaine\u2010Induced Immediate\u2010Early Gene Expression in the Nucleus Accumbens: Roles of Separate\n                    <scp>cAMP<\/scp>\n                    Sensors"],"prefix":"10.1111","volume":"170","author":[{"given":"Hai\u2010Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"Section on Molecular Neuroscience, NIMH\u2010IRP  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tabinda","family":"Salman","sequence":"additional","affiliation":[{"name":"Section on Molecular Neuroscience, NIMH\u2010IRP  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo\u2010Hua","family":"Bi","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit Molecular Targets and Medications Discovery Branch, NIDA\u2010IRP  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunny Z.","family":"Jiang","sequence":"additional","affiliation":[{"name":"Section on Molecular Neuroscience, NIMH\u2010IRP  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles R.","family":"Gerfen","sequence":"additional","affiliation":[{"name":"Office of the Scientific Director, NIMH\u2010IRP  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Lutas","sequence":"additional","affiliation":[{"name":"Neuromodulation and Motivation Section, Diabetes, Endocrinology &amp; Obesity Branch, NIDDK\u2010IRP  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqin","family":"Xu","sequence":"additional","affiliation":[{"name":"Section on Molecular Neuroscience, NIMH\u2010IRP  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng\u2010Xiong","family":"Xi","sequence":"additional","affiliation":[{"name":"Addiction Biology Unit Molecular Targets and Medications Discovery Branch, NIDA\u2010IRP  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7524-944X","authenticated-orcid":false,"given":"Lee E.","family":"Eiden","sequence":"additional","affiliation":[{"name":"Section on Molecular Neuroscience, NIMH\u2010IRP  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,29]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2016.07.010"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1039-08.2008"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2284-07.2007"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2017.00112"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2022.979078"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00056"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-4522(96)00145-5"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1579"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopsych.2009.03.014"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.npp.1301014"},{"key":"e_1_2_13_12_1","volume-title":"The Mouse Brain in Stereotaxic Coordinates","author":"Franklin K. 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