{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:53:58Z","timestamp":1790772838650,"version":"4.1.0"},"reference-count":29,"publisher":"Rockefeller University Press","issue":"12","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,11,19]]},"abstract":"<jats:p>Smoking is the leading preventable cause of disease, disability, and premature death. Nicotine, the main psychoactive drug in tobacco, is one of the most heavily used addictive substances, and its continued use is driven through activation of nicotinic acetylcholine receptors (nAChRs). Despite harmful consequences, it is difficult to quit smoking because of its positive effects on mood and cognition that are strong reinforcers contributing to addiction. Furthermore, a formidable challenge for the treatment of nicotine addiction is the high vulnerability to relapse after abstinence. There is no currently available smoking cessation product able to achieve a &amp;gt;20% smoking cessation rate after 52 wk, and there are no medications that directly target the relapse process. We report here that the \u03b17nAChR forms a protein complex with the NMDA glutamate receptor (NMDAR) through a direct protein\u2013protein interaction. Chronic nicotine exposure promotes \u03b17nAChR\u2013NMDAR complex formation. Interestingly, administration of an interfering peptide that disrupts the \u03b17nAChR\u2013NMDAR complex decreased extracellular signal-regulated kinase (ERK) activity and blocked cue-induced reinstatement of nicotine seeking in rat models of relapse, without affecting nicotine self-administration or locomotor activity. Our results may provide a novel therapeutic target for the development of medications for preventing nicotine relapse.<\/jats:p>","DOI":"10.1084\/jem.20121270","type":"journal-article","created":{"date-parts":[[2012,10,24]],"date-time":"2012-10-24T00:29:28Z","timestamp":1351038568000},"page":"2141-2147","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":53,"title":["The \u03b17nACh\u2013NMDA receptor complex is involved in cue-induced reinstatement of nicotine seeking"],"prefix":"10.1084","volume":"209","author":[{"given":"Shupeng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Centre for Addiction and Mental Health 1 ; and 2"},{"name":"Department of Psychiatry; University of Toronto, Toronto, Ontario M5T 1R8, Canada 1 ; and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ZhaoXia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Centre for Addiction and Mental Health 1 ; and 2"},{"name":"Department of Psychiatry; University of Toronto, Toronto, Ontario M5T 1R8, Canada 1 ; and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Centre for Addiction and Mental Health 1 ; and 2"},{"name":"Department of Psychiatry; University of Toronto, Toronto, Ontario M5T 1R8, Canada 1 ; and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh D.","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Centre for Addiction and Mental Health 1 ; and 2"},{"name":"Department of Psychiatry; University of Toronto, Toronto, Ontario M5T 1R8, Canada 1 ; and 2"},{"name":"Department of Neuroscience, Centre for Addiction and Mental Health 1 ; and 2"},{"name":"Department of Psychiatry; University of Toronto, Toronto, Ontario M5T 1R8, Canada 1 ; and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Centre for Addiction and Mental Health 1 ; and 2"},{"name":"Department of Psychiatry; University of Toronto, Toronto, Ontario M5T 1R8, Canada 1 ; and 2"},{"name":"Department of Neuroscience, Centre for Addiction and Mental Health 1 ; and 2"},{"name":"Department of Psychiatry; University of Toronto, Toronto, Ontario M5T 1R8, Canada 1 ; and 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2012,10,22]]},"reference":[{"key":"2023072600451077600_bib1","doi-asserted-by":"crossref","first-page":"8485","DOI":"10.1523\/JNEUROSCI.18-20-08485.1998","article-title":"Nicotine selectively enhances NMDA receptor-mediated synaptic transmission during postnatal development in sensory neocortex","volume":"18","author":"Aramakis","year":"1998","journal-title":"J. Neurosci."},{"key":"2023072600451077600_bib2","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.tips.2005.01.004","article-title":"Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation","volume":"26","author":"Bulenger","year":"2005","journal-title":"Trends Pharmacol. Sci."},{"key":"2023072600451077600_bib3","doi-asserted-by":"publisher","first-page":"9836","DOI":"10.1523\/JNEUROSCI.3497-05.2005","article-title":"Alpha7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and Src-family kinases","volume":"25","author":"Charpantier","year":"2005","journal-title":"J. Neurosci."},{"key":"2023072600451077600_bib4","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1007\/BF00589894","article-title":"Nicotine maintains robust self-administration in rats on a limited-access schedule","volume":"99","author":"Corrigall","year":"1989","journal-title":"Psychopharmacology (Berl.)."},{"key":"2023072600451077600_bib5","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/S0092-8674(00)81052-1","article-title":"Inactivation of NMDA receptors by direct interaction of calmodulin with the NR1 subunit","volume":"84","author":"Ehlers","year":"1996","journal-title":"Cell."},{"key":"2023072600451077600_bib6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00213-006-0529-6","article-title":"Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure","volume":"189","author":"Epstein","year":"2006","journal-title":"Psychopharmacology (Berl.)."},{"key":"2023072600451077600_bib7","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1016\/S0028-3908(00)00102-7","article-title":"Nicotinic receptors on hippocampal cultures can increase synaptic glutamate currents while decreasing the NMDA-receptor component","volume":"39","author":"Fisher","year":"2000","journal-title":"Neuropharmacology."},{"key":"2023072600451077600_bib8","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/383713a0","article-title":"Hippocampal synaptic transmission enhanced by low concentrations of nicotine","volume":"383","author":"Gray","year":"1996","journal-title":"Nature."},{"key":"2023072600451077600_bib9","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/npp.2008.58","article-title":"NMDA receptors regulate nicotine-enhanced brain reward function and intravenous nicotine self-administration: role of the ventral tegmental area and central nucleus of the amygdala","volume":"34","author":"Kenny","year":"2009","journal-title":"Neuropsychopharmacology."},{"key":"2023072600451077600_bib10","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1038\/nrn1517","article-title":"PDZ domain proteins of synapses","volume":"5","author":"Kim","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"2023072600451077600_bib11","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1126\/science.7569905","article-title":"Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95","volume":"269","author":"Kornau","year":"1995","journal-title":"Science."},{"key":"2023072600451077600_bib12","doi-asserted-by":"publisher","first-page":"1872","DOI":"10.1523\/JNEUROSCI.4895-05.2006","article-title":"Increased vulnerability to nicotine self-administration and relapse in alcohol-naive offspring of rats selectively bred for high alcohol intake","volume":"26","author":"L\u00ea","year":"2006","journal-title":"J. Neurosci."},{"key":"2023072600451077600_bib13","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/S0092-8674(02)00962-5","article-title":"Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor","volume":"111","author":"Lee","year":"2002","journal-title":"Cell."},{"key":"2023072600451077600_bib14","doi-asserted-by":"publisher","first-page":"S32","DOI":"10.1016\/S0893-133X(00)00155-X","article-title":"Oligomerization of dopamine and serotonin receptors","volume":"23","author":"Lee","year":"2000","journal-title":"Neuropsychopharmacology."},{"key":"2023072600451077600_bib15","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1146\/annurev.ph.56.030194.001205","article-title":"Modulation of ion channels by protein phosphorylation and dephosphorylation","volume":"56","author":"Levitan","year":"1994","journal-title":"Annu. Rev. Physiol."},{"key":"2023072600451077600_bib16","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1038\/35001232","article-title":"Direct protein-protein coupling enables cross-talk between dopamine D5 and gamma-aminobutyric acid A receptors","volume":"403","author":"Liu","year":"2000","journal-title":"Nature."},{"key":"2023072600451077600_bib17","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/nn1383","article-title":"Central amygdala ERK signaling pathway is critical to incubation of cocaine craving","volume":"8","author":"Lu","year":"2005","journal-title":"Nat. Neurosci."},{"key":"2023072600451077600_bib18","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.tins.2006.10.005","article-title":"Role of ERK in cocaine addiction","volume":"29","author":"Lu","year":"2006","journal-title":"Trends Neurosci."},{"key":"2023072600451077600_bib19","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/321519a0","article-title":"NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurones","volume":"321","author":"MacDermott","year":"1986","journal-title":"Nature."},{"key":"2023072600451077600_bib20","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1016\/j.tips.2007.11.001","article-title":"Allosteric modulation of heterodimeric G-protein-coupled receptors","volume":"28","author":"Milligan","year":"2007","journal-title":"Trends Pharmacol. Sci."},{"key":"2023072600451077600_bib21","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1038\/nm.2263","article-title":"Uncoupling the dopamine D1-D2 receptor complex exerts antidepressant-like effects","volume":"16","author":"Pei","year":"2010","journal-title":"Nat. Med."},{"key":"2023072600451077600_bib22","first-page":"1153","article-title":"Nicotine exposure reduces N-methyl-D-aspartate toxicity in the hippocampus: relation to distribution of the alpha7 nicotinic acetylcholine receptor subunit","volume":"7","author":"Prendergast","year":"2001","journal-title":"Med. Sci. Monit."},{"key":"2023072600451077600_bib23","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1016\/j.neuropharm.2008.06.057","article-title":"Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1\/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP","volume":"55","author":"Schroeder","year":"2008","journal-title":"Neuropharmacology."},{"key":"2023072600451077600_bib24","doi-asserted-by":"publisher","first-page":"7058","DOI":"10.1073\/pnas.111146298","article-title":"Molecular organization of the postsynaptic specialization","volume":"98","author":"Sheng","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072600451077600_bib25","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1523\/JNEUROSCI.2383-07.2008","article-title":"Cue-elicited reward-seeking requires extracellular signal-regulated kinase activation in the nucleus accumbens","volume":"28","author":"Shiflett","year":"2008","journal-title":"J. Neurosci."},{"key":"2023072600451077600_bib26","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s00213-008-1115-x","article-title":"Interactions between age and the aversive effects of nicotine withdrawal under mecamylamine-precipitated and spontaneous conditions in male Wistar rats","volume":"198","author":"Shram","year":"2008","journal-title":"Psychopharmacology (Berl.)."},{"key":"2023072600451077600_bib27","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/S0959-4388(97)80063-3","article-title":"Regulation of excitatory and inhibitory neurotransmitter-gated ion channels by protein phosphorylation","volume":"7","author":"Smart","year":"1997","journal-title":"Curr. Opin. Neurobiol."},{"key":"2023072600451077600_bib28","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1016\/S1040-7952(99)80005-6","article-title":"Regulation of ligand-gated ion channels by protein phosphorylation","volume":"33","author":"Swope","year":"1999","journal-title":"Adv. Second Messenger Phosphoprotein Res."},{"key":"2023072600451077600_bib29","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1038\/385439a0","article-title":"Competitive binding of alpha-actinin and calmodulin to the NMDA receptor","volume":"385","author":"Wyszynski","year":"1997","journal-title":"Nature."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/209\/12\/2141\/1742865\/jem_20121270.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/209\/12\/2141\/1742865\/jem_20121270.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,26]],"date-time":"2023-07-26T00:45:36Z","timestamp":1690332336000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/209\/12\/2141\/41227\/The-7nACh-NMDA-receptor-complex-is-involved-in-cue"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,10,22]]},"references-count":29,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2012,11,19]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20121270","relation":{},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2012,10,22]]}}}