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Activation of PKA signaling is mediated by Gi-\u03b2\u03b3 dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP\/PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by \u03b2\u03b3 dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.<\/jats:p>","DOI":"10.1073\/pnas.2336093100","type":"journal-article","created":{"date-parts":[[2003,11,25]],"date-time":"2003-11-25T20:59:06Z","timestamp":1069793946000},"page":"14379-14384","update-policy":"http:\/\/dx.doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":69,"title":["Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-\u03b2\u03b3 dimers"],"prefix":"10.1073","volume":"100","author":[{"given":"Lina","family":"Yao","sequence":"first","affiliation":[{"name":"Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608; and Departments of Neurology and Cellular and Molecular Pharmacology, Neuroscience Graduate Program and The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA 94110"}]},{"given":"Peidong","family":"Fan","sequence":"additional","affiliation":[{"name":"Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608; and Departments of Neurology and Cellular and Molecular Pharmacology, Neuroscience Graduate Program and The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA 94110"}]},{"given":"Zhan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608; and Departments of Neurology and Cellular and Molecular Pharmacology, Neuroscience Graduate Program and The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA 94110"}]},{"given":"William S.","family":"Mailliard","sequence":"additional","affiliation":[{"name":"Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608; and Departments of Neurology and Cellular and Molecular Pharmacology, Neuroscience Graduate Program and The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA 94110"}]},{"given":"Adrienne S.","family":"Gordon","sequence":"additional","affiliation":[{"name":"Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608; and Departments of Neurology and Cellular and Molecular Pharmacology, Neuroscience Graduate Program and The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA 94110"}]},{"given":"Ivan","family":"Diamond","sequence":"additional","affiliation":[{"name":"Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608; and Departments of Neurology and Cellular and Molecular Pharmacology, Neuroscience Graduate Program and The Wheeler Center for the Neurobiology of Addiction, University of California, San Francisco, CA 94110"}]}],"member":"341","published-online":{"date-parts":[[2003,11,6]]},"reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/19208"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/35053570"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/35094560"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(01)00259-5"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1962211"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/356159a0"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)37587-7"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.52.2.181"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00763-8"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.72.8.3092"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.5.2794"},{"key":"e_1_3_2_12_2","unstructured":"Lim F. & Neve R. 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