{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T12:25:53Z","timestamp":1790079953141,"version":"4.0.1"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,21]],"date-time":"2017-04-21T00:00:00Z","timestamp":1492732800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,21]],"date-time":"2017-04-21T00:00:00Z","timestamp":1492732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Relapse to drug seeking can be caused by exposure to drug-associated cues, provoking drug craving even after prolonged abstinence. Recent studies demonstrated that AMP-activated protein kinase (AMPK) regulates neuronal morphology and membrane excitability in neurons. Here, we investigated the role of AMPK activity in the nucleus accumbens (NAc) in relapse to cocaine seeking. We found that exposure to drug-related cues reinstated cocaine-seeking behavior and increased AMPK and p70s6k phosphorylation in the NAc core but not shell. Augmenting AMPK activity by intra-NAc core infusions of the AMPK activator 5-amino-1-\u03b2-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) or adenovirus expressing constitutively active subunits of AMPK decreased cue-induced reinstatement of cocaine seeking and inhibited the mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal-regulated kinase 1\/2 (ERK1\/2) pathways. In contrast, inhibition of AMPK activity by intra-NAc core infusions of the AMPK inhibitor compound C or adenovirus expressing dominant-negative subunits of AMPK increased cue-induced reinstatement of cocaine seeking and enhanced mTORC1 and ERK1\/2 activity. The regulation of AMPK activity in the NAc shell had no effect on cue-induced cocaine seeking. Altogether, these results indicate that AMPK activity in the NAc core is critical for the cue-induced reinstatement of cocaine seeking, which may be mediated by mTORC1 and ERK1\/2 signaling.<\/jats:p>","DOI":"10.1038\/s41598-017-01043-5","type":"journal-article","created":{"date-parts":[[2017,4,13]],"date-time":"2017-04-13T11:40:39Z","timestamp":1492083639000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["AMPK signaling in the nucleus accumbens core mediates cue-induced reinstatement of cocaine seeking"],"prefix":"10.1038","volume":"7","author":[{"given":"Xue-Jiao","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Xiao","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Jian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Feng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Shi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,21]]},"reference":[{"key":"1043_CR1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1007\/s12630-016-0771-2","volume":"64","author":"B MacNicol","year":"2017","unstructured":"MacNicol, B. The biology of addiction. Can J Anaesth 64, 141\u2013148, doi:10.1007\/s12630-016-0771-2 (2017).","journal-title":"Can J Anaesth"},{"key":"1043_CR2","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.tins.2010.02.002","volume":"33","author":"SJ Russo","year":"2010","unstructured":"Russo, S. J. et al. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci 33, 267\u2013276, doi:10.1016\/j.tins.2010.02.002 (2010).","journal-title":"Trends Neurosci"},{"key":"1043_CR3","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1016\/j.cell.2015.07.046","volume":"162","author":"ND Volkow","year":"2015","unstructured":"Volkow, N. D. & Morales, M. The brain on drugs: from reward to addiction. Cell 162, 712\u2013725, doi:10.1016\/j.cell.2015.07.046 (2015).","journal-title":"Cell"},{"key":"1043_CR4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1176\/ajp.156.1.11","volume":"156","author":"AR Childress","year":"1999","unstructured":"Childress, A. R. et al. Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156, 11\u201318, doi:10.1176\/ajp.156.1.11 (1999).","journal-title":"Am J Psychiatry"},{"key":"1043_CR5","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.tins.2011.06.001","volume":"34","author":"CL Pickens","year":"2011","unstructured":"Pickens, C. L. et al. Neurobiology of the incubation of drug craving. Trends Neurosci 34, 411\u2013420, doi:10.1016\/j.tins.2011.06.001 (2011).","journal-title":"Trends Neurosci"},{"key":"1043_CR6","doi-asserted-by":"publisher","first-page":"5436","DOI":"10.1523\/JNEUROSCI.5884-10.2011","volume":"31","author":"YQ Li","year":"2011","unstructured":"Li, Y. Q. et al. Inhibition of PKM\u03b6 in nucleus accumbens core abolishes long-term drug reward memory. J Neurosci 31, 5436\u20135446, doi:10.1523\/JNEUROSCI.5884-10.2011 (2011).","journal-title":"J Neurosci"},{"key":"1043_CR7","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1016\/j.biopsych.2008.11.025","volume":"65","author":"SX Li","year":"2009","unstructured":"Li, S. X. et al. Circadian alteration in neurobiology during 30 days of abstinence in heroin users. Biol Psychiatry 65, 905\u2013912, doi:10.1016\/j.biopsych.2008.11.025 (2009).","journal-title":"Biol Psychiatry"},{"key":"1043_CR8","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s00213-002-1224-x","volume":"168","author":"Y Shaham","year":"2003","unstructured":"Shaham, Y., Shalev, U., Lu, L., De Wit, H. & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168, 3\u201320, doi:10.1007\/s00213-002-1224-x (2003).","journal-title":"Psychopharmacology (Berl)"},{"key":"1043_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00213-006-0529-6","volume":"189","author":"DH Epstein","year":"2006","unstructured":"Epstein, D. H., Preston, K. L., Stewart, J. & Shaham, Y. Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology (Berl) 189, 1\u201316, doi:10.1007\/s00213-006-0529-6 (2006).","journal-title":"Psychopharmacology (Berl)"},{"key":"1043_CR10","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s00213-003-1441-y","volume":"168","author":"JL Katz","year":"2003","unstructured":"Katz, J. L. & Higgins, S. T. The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology (Berl) 168, 21\u201330, doi:10.1007\/s00213-003-1441-y (2003).","journal-title":"Psychopharmacology (Berl)"},{"key":"1043_CR11","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1176\/appi.ajp.2010.10040499","volume":"168","author":"XL Zhang","year":"2011","unstructured":"Zhang, X. L. et al. Effects of stress on decision-making deficits in formerly heroin-dependent patients after different durations of abstinence. Am J Psychiatry 168, 610\u2013616, doi:10.1176\/appi.ajp.2010.10040499 (2011).","journal-title":"Am J Psychiatry"},{"key":"1043_CR12","doi-asserted-by":"publisher","first-page":"2754078","DOI":"10.1155\/2016\/2754078","volume":"2016","author":"MK Huynh","year":"2016","unstructured":"Huynh, M. K., Kinyua, A. W., Yang, D. J. & Kim, K. W. Hypothalamic AMPK as a regulator of energy homeostasis. Neural Plast 2016, 2754078\u201312, doi:10.1155\/2016\/2754078 (2016).","journal-title":"Neural Plast"},{"key":"1043_CR13","doi-asserted-by":"publisher","unstructured":"Li, J., Li, S., Wang, F. & Xin, F. Structural and biochemical insights into the allosteric activation mechanism of AMP-activated protein kinase. Chem Biol Drug Des in press, doi:10.1111\/cbdd.12897 (2016).","DOI":"10.1111\/cbdd.12897"},{"key":"1043_CR14","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1038\/ncb2329","volume":"13","author":"MM Mihaylova","year":"2011","unstructured":"Mihaylova, M. M. & Shaw, R. J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13, 1016\u20131023, doi:10.1038\/ncb2329 (2011).","journal-title":"Nat Cell Biol"},{"key":"1043_CR15","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1038\/nature09706","volume":"470","author":"W Mair","year":"2011","unstructured":"Mair, W. et al. Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature 470, 404\u2013408, doi:10.1038\/nature09706 (2011).","journal-title":"Nature"},{"key":"1043_CR16","doi-asserted-by":"publisher","first-page":"e245","DOI":"10.1038\/emm.2016.81","volume":"48","author":"SM Jeon","year":"2016","unstructured":"Jeon, S. M. Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48, e245, doi:10.1038\/emm.2016.81 (2016).","journal-title":"Exp Mol Med"},{"key":"1043_CR17","doi-asserted-by":"publisher","first-page":"1697","DOI":"10.1042\/CS20160048","volume":"130","author":"PB Martinez de Morentin","year":"2016","unstructured":"Martinez de Morentin, P. B., Urisarri, A., Couce, M. L. & Lopez, M. Molecular mechanisms of appetite and obesity: a role for brain AMPK. Clin Sci (Lond) 130, 1697\u20131709, doi:10.1042\/CS20160048 (2016).","journal-title":"Clin Sci (Lond)"},{"key":"1043_CR18","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/nature02440","volume":"428","author":"Y Minokoshi","year":"2004","unstructured":"Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569\u2013574, doi:10.1038\/nature02440 (2004).","journal-title":"Nature"},{"key":"1043_CR19","doi-asserted-by":"publisher","first-page":"2009","DOI":"10.1080\/15548627.2016.1215382","volume":"12","author":"TS Oh","year":"2016","unstructured":"Oh, T. S., Cho, H., Cho, J. H., Yu, S. W. & Kim, E. K. Hypothalamic AMPK-induced autophagy increases food intake by regulating NPY and POMC expression. Autophagy 12, 2009\u20132025, doi:10.1080\/15548627.2016.1215382 (2016).","journal-title":"Autophagy"},{"key":"1043_CR20","doi-asserted-by":"publisher","first-page":"896","DOI":"10.2174\/1871527315666160815165806","volume":"15","author":"TS Oh","year":"2016","unstructured":"Oh, T. S., Jeon, Y., Kim, S. & Kim, E. K. Hypothalamic AMP-activated protein kinase as a regulator of food intake and energy balance. CNS Neurol Disord Drug Targets 15, 896\u2013909, doi:10.2174\/1871527315666160815165806 (2016).","journal-title":"CNS Neurol Disord Drug Targets"},{"key":"1043_CR21","doi-asserted-by":"publisher","first-page":"6772","DOI":"10.1073\/pnas.0811331106","volume":"106","author":"S Chung","year":"2009","unstructured":"Chung, S. et al. The melanin-concentrating hormone system modulates cocaine reward. Proc Natl Acad Sci USA 106, 6772\u20136777, doi:10.1073\/pnas.0811331106 (2009).","journal-title":"Proc Natl Acad Sci USA"},{"key":"1043_CR22","doi-asserted-by":"publisher","first-page":"1767","DOI":"10.1017\/S1461145713000072","volume":"16","author":"LL Sun","year":"2013","unstructured":"Sun, L. L. et al. Role of melanin-concentrating hormone in the nucleus accumbens shell in rats behaviourally sensitized to methamphetamine. Int J Neuropsychopharmacol 16, 1767\u20131780, doi:10.1017\/S1461145713000072 (2013).","journal-title":"Int J Neuropsychopharmacol"},{"key":"1043_CR23","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.pbb.2013.02.010","volume":"105","author":"G Sorensen","year":"2013","unstructured":"Sorensen, G., Wortwein, G., Fink-Jensen, A. & Woldbye, D. P. Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference. Pharmacol Biochem Behav 105, 151\u2013156, doi:10.1016\/j.pbb.2013.02.010 (2013).","journal-title":"Pharmacol Biochem Behav"},{"key":"1043_CR24","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1007\/s00213-010-1891-y","volume":"211","author":"A Cippitelli","year":"2010","unstructured":"Cippitelli, A. et al. Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats. Psychopharmacology (Berl) 211, 367\u2013375, doi:10.1007\/s00213-010-1891-y (2010).","journal-title":"Psychopharmacology (Berl)"},{"key":"1043_CR25","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.neuron.2006.12.015","volume":"53","author":"N Kuramoto","year":"2007","unstructured":"Kuramoto, N. et al. Phospho-dependent functional modulation of GABA(B) receptors by the metabolic sensor AMP-dependent protein kinase. Neuron 53, 233\u2013247, doi:10.1016\/j.neuron.2006.12.015 (2007).","journal-title":"Neuron"},{"key":"1043_CR26","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1126\/science.1201678","volume":"332","author":"S Amato","year":"2011","unstructured":"Amato, S. et al. AMP-activated protein kinase regulates neuronal polarization by interfering with PI 3-kinase localization. Science 332, 247\u2013251, doi:10.1126\/science.1201678 (2011).","journal-title":"Science"},{"key":"1043_CR27","doi-asserted-by":"publisher","first-page":"18132","DOI":"10.1073\/pnas.1106201108","volume":"108","author":"N Ikematsu","year":"2011","unstructured":"Ikematsu, N. et al. Phosphorylation of the voltage-gated potassium channel Kv2.1 by AMP-activated protein kinase regulates membrane excitability. Proc Natl Acad Sci USA 108, 18132\u201318137, doi:10.1073\/pnas.1106201108 (2011).","journal-title":"Proc Natl Acad Sci USA"},{"key":"1043_CR28","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1093\/hmg\/ddu497","volume":"24","author":"YJ Liu","year":"2015","unstructured":"Liu, Y. J. et al. Activation of AMP-activated protein kinase \u03b11 mediates mislocalization of TDP-43 in amyotrophic lateral sclerosis. Hum Mol Genet 24, 787\u2013801, doi:10.1093\/hmg\/ddu497 (2015).","journal-title":"Hum Mol Genet"},{"key":"1043_CR29","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1083\/jcb.201105010","volume":"194","author":"TC Ju","year":"2011","unstructured":"Ju, T. C. et al. Nuclear translocation of AMPK-\u03b11 potentiates striatal neurodegeneration in Huntington\u2019s disease. J Cell Biol 194, 209\u2013227, doi:10.1083\/jcb.201105010 (2011).","journal-title":"J Cell Biol"},{"key":"1043_CR30","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1016\/j.neuron.2013.02.003","volume":"78","author":"G Mairet-Coello","year":"2013","unstructured":"Mairet-Coello, G. et al. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of A\u03b2 oligomers through Tau phosphorylation. Neuron 78, 94\u2013108, doi:10.1016\/j.neuron.2013.02.003 (2013).","journal-title":"Neuron"},{"key":"1043_CR31","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1016\/j.cell.2011.07.039","volume":"146","author":"Y Yang","year":"2011","unstructured":"Yang, Y., Atasoy, D., Su, H. H. & Sternson, S. M. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992\u20131003, doi:10.1016\/j.cell.2011.07.039 (2011).","journal-title":"Cell"},{"key":"1043_CR32","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.neuron.2016.05.025","volume":"91","author":"D Kong","year":"2016","unstructured":"Kong, D. et al. A postsynaptic AMPK\u2013>p21-activated kinase pathway drives fasting-induced synaptic plasticity in AgRP neurons. Neuron 91, 25\u201333, doi:10.1016\/j.neuron.2016.05.025 (2016).","journal-title":"Neuron"},{"key":"1043_CR33","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1038\/nn.3147","volume":"15","author":"MO Dietrich","year":"2012","unstructured":"Dietrich, M. O. et al. AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors. Nat Neurosci 15, 1108\u20131110, doi:10.1038\/nn.3147 (2012).","journal-title":"Nat Neurosci"},{"key":"1043_CR34","doi-asserted-by":"publisher","first-page":"1849","DOI":"10.1038\/npp.2015.355","volume":"41","author":"Y Han","year":"2016","unstructured":"Han, Y. et al. AMPK signaling in the dorsal hippocampus negatively regulates contextual fear memory formation. Neuropsychopharmacology 41, 1849\u20131864, doi:10.1038\/npp.2015.355 (2016).","journal-title":"Neuropsychopharmacology"},{"key":"1043_CR35","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.2147\/NDT.S45963","volume":"9","author":"GC Quintero","year":"2013","unstructured":"Quintero, G. C. Role of nucleus accumbens glutamatergic plasticity in drug addiction. Neuropsychiatr Dis Treat 9, 1499\u20131512, doi:10.2147\/NDT.S45963 (2013).","journal-title":"Neuropsychiatr Dis Treat"},{"key":"1043_CR36","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/nrn3381","volume":"14","author":"SJ Russo","year":"2013","unstructured":"Russo, S. J. & Nestler, E. J. The brain reward circuitry in mood disorders. Nat Rev Neurosci 14, 609\u2013625, doi:10.1038\/nrn3381 (2013).","journal-title":"Nat Rev Neurosci"},{"key":"1043_CR37","doi-asserted-by":"publisher","first-page":"466","DOI":"10.3389\/fncel.2014.00466","volume":"8","author":"AN van Huijstee","year":"2014","unstructured":"van Huijstee, A. N. & Mansvelder, H. D. Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction. Front Cell Neurosci 8, 466, doi:10.3389\/fncel.2014.00466 (2014).","journal-title":"Front Cell Neurosci"},{"key":"1043_CR38","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1007\/s00213-004-1895-6","volume":"176","author":"RA Fuchs","year":"2004","unstructured":"Fuchs, R. A., Evans, K. A., Parker, M. C. & See, R. E. Differential involvement of the core and shell subregions of the nucleus accumbens in conditioned cue-induced reinstatement of cocaine seeking in rats. Psychopharmacology (Berl) 176, 459\u2013465, doi:10.1007\/s00213-004-1895-6 (2004).","journal-title":"Psychopharmacology (Berl)"},{"key":"1043_CR39","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1523\/JNEUROSCI.23-08-03531.2003","volume":"23","author":"K McFarland","year":"2003","unstructured":"McFarland, K., Lapish, C. C. & Kalivas, P. W. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 23, 3531\u20133537 (2003).","journal-title":"J Neurosci"},{"key":"1043_CR40","doi-asserted-by":"publisher","first-page":"7167","DOI":"10.1523\/JNEUROSCI.1581-04.2004","volume":"24","author":"P Di Ciano","year":"2004","unstructured":"Di Ciano, P. & Everitt, B. J. Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats. J Neurosci 24, 7167\u20137173, doi:10.1523\/JNEUROSCI.1581-04.2004 (2004).","journal-title":"J Neurosci"},{"key":"1043_CR41","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1038\/nn1579","volume":"8","author":"BJ Everitt","year":"2005","unstructured":"Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8, 1481\u20131489, doi:10.1038\/nn1579 (2005).","journal-title":"Nat Neurosci"},{"key":"1043_CR42","doi-asserted-by":"publisher","first-page":"4982","DOI":"10.1523\/JNEUROSCI.0005-12.2012","volume":"32","author":"JM Bossert","year":"2012","unstructured":"Bossert, J. M. et al. Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking. J Neurosci 32, 4982\u20134991, doi:10.1523\/JNEUROSCI.0005-12.2012 (2012).","journal-title":"J Neurosci"},{"key":"1043_CR43","doi-asserted-by":"publisher","first-page":"3233","DOI":"10.1098\/rstb.2008.0090","volume":"363","author":"HS Crombag","year":"2008","unstructured":"Crombag, H. S., Bossert, J. M., Koya, E. & Shaham, Y. Review. Context-induced relapse to drug seeking: a review. Philos Trans R Soc Lond B Biol Sci 363, 3233\u20133243, doi:10.1098\/rstb.2008.0090 (2008).","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"1043_CR44","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.devcel.2009.01.005","volume":"16","author":"B Dasgupta","year":"2009","unstructured":"Dasgupta, B. & Milbrandt, J. AMP-activated protein kinase phosphorylates retinoblastoma protein to control mammalian brain development. Dev Cell 16, 256\u2013270, doi:10.1016\/j.devcel.2009.01.005 (2009).","journal-title":"Dev Cell"},{"key":"1043_CR45","doi-asserted-by":"publisher","first-page":"5849","DOI":"10.1073\/pnas.1013660108","volume":"108","author":"T Williams","year":"2011","unstructured":"Williams, T., Courchet, J., Viollet, B., Brenman, J. E. & Polleux, F. AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress. Proc Natl Acad Sci USA 108, 5849\u20135854, doi:10.1073\/pnas.1013660108 (2011).","journal-title":"Proc Natl Acad Sci USA"},{"key":"1043_CR46","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.molcel.2013.08.044","volume":"52","author":"CH Shen","year":"2013","unstructured":"Shen, C. H. et al. Phosphorylation of BRAF by AMPK impairs BRAF-KSR1 association and cell proliferation. Mol Cell 52, 161\u2013172, doi:10.1016\/j.molcel.2013.08.044 (2013).","journal-title":"Mol Cell"},{"key":"1043_CR47","doi-asserted-by":"publisher","first-page":"2831","DOI":"10.1210\/en.2011-1967","volume":"153","author":"PP Kayampilly","year":"2012","unstructured":"Kayampilly, P. P. & Menon, K. M. AMPK activation by dihydrotestosterone reduces FSH-stimulated cell proliferation in rat granulosa cells by inhibiting ERK signaling pathway. Endocrinology 153, 2831\u20132838, doi:10.1210\/en.2011-1967 (2012).","journal-title":"Endocrinology"},{"key":"1043_CR48","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1111\/bph.12124","volume":"169","author":"SL Hwang","year":"2013","unstructured":"Hwang, S. L. et al. Inhibitory cross-talk between the AMPK and ERK pathways mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle. Br J Pharmacol 169, 69\u201381, doi:10.1111\/bph.12124 (2013).","journal-title":"Br J Pharmacol"},{"key":"1043_CR49","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1016\/S0092-8674(04)00115-1","volume":"116","author":"RJ Kelleher 3rd","year":"2004","unstructured":"Kelleher, R. J. 3rd, Govindarajan, A., Jung, H. Y., Kang, H. & Tonegawa, S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467\u2013479, doi:10.1016\/S0092-8674(04)00115-1 (2004).","journal-title":"Cell"},{"key":"1043_CR50","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.nlm.2014.12.014","volume":"119","author":"MG Giovannini","year":"2015","unstructured":"Giovannini, M. G., Lana, D. & Pepeu, G. The integrated role of ACh, ERK and mTOR in the mechanisms of hippocampal inhibitory avoidance memory. Neurobiol Learn Mem 119, 18\u201333, doi:10.1016\/j.nlm.2014.12.014 (2015).","journal-title":"Neurobiol Learn Mem"},{"key":"1043_CR51","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.neuron.2008.10.055","volume":"61","author":"M Costa-Mattioli","year":"2009","unstructured":"Costa-Mattioli, M., Sossin, W. S., Klann, E. & Sonenberg, N. Translational control of long-lasting synaptic plasticity and memory. Neuron 61, 10\u201326, doi:10.1016\/j.neuron.2008.10.055 (2009).","journal-title":"Neuron"},{"key":"1043_CR52","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.neuron.2004.09.013","volume":"44","author":"RJ Kelleher 3rd","year":"2004","unstructured":"Kelleher, R. J. 3rd, Govindarajan, A. & Tonegawa, S. Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 59\u201373, doi:10.1016\/j.neuron.2004.09.013 (2004).","journal-title":"Neuron"},{"key":"1043_CR53","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/nn1383","volume":"8","author":"L Lu","year":"2005","unstructured":"Lu, L. et al. Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8, 212\u2013219, doi:10.1038\/nn1383 (2005).","journal-title":"Nat Neurosci"},{"key":"1043_CR54","doi-asserted-by":"publisher","first-page":"12632","DOI":"10.1523\/JNEUROSCI.1264-10.2010","volume":"30","author":"X Wang","year":"2010","unstructured":"Wang, X. et al. Nucleus accumbens core mammalian target of rapamycin signaling pathway is critical for cue-induced reinstatement of cocaine seeking in rats. J Neurosci 30, 12632\u201312641, doi:10.1523\/JNEUROSCI.1264-10.2010 (2010).","journal-title":"J Neurosci"},{"key":"1043_CR55","doi-asserted-by":"crossref","unstructured":"Li, S. X. et al. Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Mol Psychiatry in press (2017).","DOI":"10.1038\/mp.2017.85"},{"key":"1043_CR56","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1001\/jamapsychiatry.2016.3907","volume":"74","author":"YX Xue","year":"2017","unstructured":"Xue, Y. X. et al. Effect of selective inhibition of reactivated nicotine-associated memories with propranolol on nicotine craving. JAMA Psychiatry 74, 224\u2013232, doi:10.1001\/jamapsychiatry.2016.3907 (2017).","journal-title":"JAMA Psychiatry"},{"key":"1043_CR57","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1523\/JNEUROSCI.17-07-02605.1997","volume":"17","author":"Y Shaham","year":"1997","unstructured":"Shaham, Y. et al. Corticotropin-releasing factor, but not corticosterone, is involved in stress-induced relapse to heroin-seeking in rats. J Neurosci 17, 2605\u20132614 (1997).","journal-title":"J Neurosci"},{"key":"1043_CR58","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.biopsych.2009.02.009","volume":"66","author":"L Lu","year":"2009","unstructured":"Lu, L. et al. Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving. Biol Psychiatry 66, 137\u2013145, doi:10.1016\/j.biopsych.2009.02.009 (2009).","journal-title":"Biol Psychiatry"},{"key":"1043_CR59","unstructured":"Paxinos, G. & Watson, C. The rat brain in stereotaxic coordinates: the new coronal set, 5th edn. New York: Academic Press (2005)."},{"key":"1043_CR60","doi-asserted-by":"publisher","first-page":"4901","DOI":"10.1523\/JNEUROSCI.3554-05.2006","volume":"26","author":"A Zangen","year":"2006","unstructured":"Zangen, A., Solinas, M., Ikemoto, S., Goldberg, S. R. & Wise, R. A. Two brain sites for cannabinoid reward. J Neurosci 26, 4901\u20134907, doi:10.1523\/JNEUROSCI.3554-05.2006 (2006).","journal-title":"J Neurosci"},{"key":"1043_CR61","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/npp.2012.243","volume":"38","author":"ZY Ren","year":"2013","unstructured":"Ren, Z. Y. et al. A critical role for protein degradation in the nucleus accumbens core in cocaine reward memory. Neuropsychopharmacology 38, 778\u2013790, doi:10.1038\/npp.2012.243 (2013).","journal-title":"Neuropsychopharmacology"},{"key":"1043_CR62","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1016\/S1097-2765(01)00251-9","volume":"7","author":"J Mu","year":"2001","unstructured":"Mu, J., Brozinick, J. T. Jr., Valladares, O., Bucan, M. & Birnbaum, M. J. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol Cell 7, 1085\u20131094, doi:10.1016\/S1097-2765(01)00251-9 (2001).","journal-title":"Mol Cell"},{"key":"1043_CR63","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1016\/j.molcel.2005.03.027","volume":"18","author":"RG Jones","year":"2005","unstructured":"Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18, 283\u2013293, doi:10.1016\/j.molcel.2005.03.027 (2005).","journal-title":"Mol Cell"},{"key":"1043_CR64","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1016\/j.ejphar.2013.08.006","volume":"718","author":"M Ikegami","year":"2013","unstructured":"Ikegami, M. et al. Olanzapine induces glucose intolerance through the activation of AMPK in the mouse hypothalamus. Eur J Pharmacol 718, 376\u2013382, doi:10.1016\/j.ejphar.2013.08.006 (2013).","journal-title":"Eur J Pharmacol"},{"key":"1043_CR65","doi-asserted-by":"publisher","first-page":"10010","DOI":"10.1523\/JNEUROSCI.0934-14.2014","volume":"34","author":"M Jian","year":"2014","unstructured":"Jian, M. et al. eIF2\u03b1 dephosphorylation in basolateral amygdala mediates reconsolidation of drug memory. J Neurosci 34, 10010\u201310021, doi:10.1523\/JNEUROSCI.0934-14.2014 (2014).","journal-title":"J Neurosci"},{"key":"1043_CR66","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1126\/science.1215070","volume":"336","author":"YX Xue","year":"2012","unstructured":"Xue, Y. X. et al. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science 336, 241\u2013245, doi:10.1126\/science.1215070 (2012).","journal-title":"Science"},{"key":"1043_CR67","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1038\/nn1929","volume":"10","author":"DL Graham","year":"2007","unstructured":"Graham, D. L. et al. Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci 10, 1029\u20131037, doi:10.1038\/nn1929 (2007).","journal-title":"Nat Neurosci"},{"key":"1043_CR68","doi-asserted-by":"publisher","first-page":"7675","DOI":"10.1038\/ncomms8675","volume":"6","author":"YX Luo","year":"2015","unstructured":"Luo, Y. X. et al. A novel UCS memory retrieval-extinction procedure to inhibit relapse to drug seeking. Nat Commun 6, 7675, doi:10.1038\/ncomms8675 (2015).","journal-title":"Nat Commun"},{"key":"1043_CR69","doi-asserted-by":"crossref","unstructured":"Xu, L. Z. et al. BDNF-GSK-3\u03b2-\u03b2-catenin pathway in the mPFC is involved in antidepressant-like effects of Morinda officinalis oligosaccharides in rats. Int J Neuropsychopharmacol pii: pyw088 (2016).","DOI":"10.1093\/ijnp\/pyw088"},{"key":"1043_CR70","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1038\/npp.2014.42","volume":"39","author":"N Chai","year":"2014","unstructured":"Chai, N. et al. Delayed noradrenergic activation in the dorsal hippocampus promotes the long-term persistence of extinguished fear. Neuropsychopharmacology 39, 1933\u20131945, doi:10.1038\/npp.2014.42 (2014).","journal-title":"Neuropsychopharmacology"},{"key":"1043_CR71","doi-asserted-by":"publisher","first-page":"22096","DOI":"10.1038\/srep22096","volume":"6","author":"C Chen","year":"2016","unstructured":"Chen, C. et al. Epigenetic modification of PKM\u03b6 rescues aging-related cognitive impairment. Sci Rep 6, 22096, doi:10.1038\/srep22096 (2016).","journal-title":"Sci Rep"},{"key":"1043_CR72","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1038\/npp.2016.58","volume":"41","author":"RX Zhang","year":"2016","unstructured":"Zhang, R. X. et al. EphB2 in the medial prefrontal cortex regulates vulnerability to stress. Neuropsychopharmacology 41, 2541\u20132556, doi:10.1038\/npp.2016.58 (2016).","journal-title":"Neuropsychopharmacology"}],"updated-by":[{"DOI":"10.1038\/s41598-020-61259-w","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,3,6]],"date-time":"2020-03-06T00:00:00Z","timestamp":1583452800000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01043-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01043-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01043-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T03:39:42Z","timestamp":1671766782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-01043-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,21]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["1043"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-01043-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,21]]},"assertion":[{"value":"30 January 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2020","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"An amendment to this paper has been published and can be accessed via a link at the top of the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"1038"}}