{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,5]],"date-time":"2026-07-05T08:37:57Z","timestamp":1783240677333,"version":"3.54.6"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T00:00:00Z","timestamp":1611187200000},"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":["J Mol Neurosci"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Among the neuroadaptations underlying the expression of cocaine-induced behaviors are modifications in glutamate-mediated signaling and synaptic plasticity via activation of mitogen-activated protein kinases (MAPKs) within the nucleus accumbens (NAc). We hypothesized that exposure to cocaine leads to alterations in MAPK signaling in NAc neurons, which facilitates changes in the glutamatergic system and thus behavioral changes. We have previously shown that following withdrawal from cocaine-induced behavioral sensitization (BS), an increase in glutamate receptor expression and elevated MAPK signaling was evident. Here, we set out to determine the time course and behavioral consequences of inhibition of extracellular signal-regulated kinase (ERK) or NMDA receptors following withdrawal from BS. We found that inhibiting ERK by microinjection of U0126 into the NAc at 1 or 6\u00a0days following withdrawal from BS did not affect the expression of BS when challenged with cocaine at 14\u00a0days. However, inhibition of ERK 1 day before the cocaine challenge abolished the expression of BS. We also inhibited NR2B-containing NMDA receptors in the NAc by microinjection of ifenprodil into the NAc following withdrawal from BS, which had no effect on the expression of BS. However, microinjection of ifenprodil to the NAc 1 day before challenge attenuated the expression of BS similar to ERK inhibition. These results suggest that following a prolonged period of withdrawal, NR2B-containing NMDA receptors and ERK activity play a critical role in the expression of cocaine behavioral sensitization.<\/jats:p>","DOI":"10.1007\/s12031-021-01799-6","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T17:03:33Z","timestamp":1611248613000},"page":"2229-2236","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Potentiated Response of ERK\/MAPK Signaling is Associated with Prolonged Withdrawal from Cocaine Behavioral Sensitization"],"prefix":"10.1007","volume":"71","author":[{"given":"Alexey","family":"Bingor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matityahu","family":"Azriel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavi","family":"Amiad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2372-2957","authenticated-orcid":false,"given":"Rami","family":"Yaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,21]]},"reference":[{"key":"1799_CR1","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1038\/2836","volume":"1","author":"CM Atkins","year":"1998","unstructured":"Atkins CM, Selcher JC, Petraitis JJ, Trzaskos JM, Sweatt JD (1998) The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1:602\u2013609. https:\/\/doi.org\/10.1038\/2836","journal-title":"Nat Neurosci"},{"key":"1799_CR2","doi-asserted-by":"publisher","first-page":"4707","DOI":"10.1523\/JNEUROSCI.16-15-04707.1996","volume":"16","author":"MT Berhow","year":"1996","unstructured":"Berhow MT, Hiroi N, Nestler EJ (1996) Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J Neurosci 16:4707\u20134715. https:\/\/doi.org\/10.1523\/JNEUROSCI.16-15-04707.1996","journal-title":"J Neurosci"},{"key":"1799_CR3","doi-asserted-by":"publisher","first-page":"10621","DOI":"10.1523\/jneurosci.2163-07.2007","volume":"27","author":"AC Boudreau","year":"2007","unstructured":"Boudreau AC, Reimers JM, Milovanovic M, Wolf ME (2007) Cell surface AMPA receptors in the rat nucleus accumbens increase during cocaine withdrawal but internalize after cocaine challenge in association with altered activation of mitogen-activated protein kinases. J Neurosci 27:10621\u201310635. https:\/\/doi.org\/10.1523\/jneurosci.2163-07.2007","journal-title":"J Neurosci"},{"key":"1799_CR4","doi-asserted-by":"publisher","first-page":"9144","DOI":"10.1523\/JNEUROSCI.2252-05.2005","volume":"25","author":"AC Boudreau","year":"2005","unstructured":"Boudreau AC, Wolf ME (2005) Behavioral sensitization to cocaine is associated with increased AMPA receptor surface expression in the nucleus accumbens. J Neurosci 25:9144\u20139151. https:\/\/doi.org\/10.1523\/JNEUROSCI.2252-05.2005","journal-title":"J Neurosci"},{"key":"1799_CR5","doi-asserted-by":"publisher","first-page":"8114","DOI":"10.1073\/pnas.0711755105","volume":"105","author":"S Carnicella","year":"2008","unstructured":"Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D (2008) GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc Natl Acad Sci U S A 105:8114\u20138119. https:\/\/doi.org\/10.1073\/pnas.0711755105","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1799_CR6","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1038\/nature06995","volume":"454","author":"KL Conrad","year":"2008","unstructured":"Conrad KL, Tseng KY, Uejima JL, Reimers JM, Heng L-J, Shaham Y et al (2008) Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454:118\u2013121. https:\/\/doi.org\/10.1038\/nature06995","journal-title":"Nature"},{"key":"1799_CR7","doi-asserted-by":"publisher","first-page":"10867","DOI":"10.1523\/JNEUROSCI.1821-17.2017","volume":"37","author":"Y Dong","year":"2017","unstructured":"Dong Y, Taylor JR, Wolf ME, Shaham Y (2017) Circuit and synaptic plasticity mechanisms of drug relapse. J Neurosci 37:10867\u201310876. https:\/\/doi.org\/10.1523\/JNEUROSCI.1821-17.2017","journal-title":"J Neurosci"},{"key":"1799_CR8","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.1016\/S0960-894X(98)00522-8","volume":"8","author":"JV Duncia","year":"1998","unstructured":"Duncia JV, Santella JB, Higley CA, Pitts WJ, Wityak J, Frietze WE et al (1998) MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett 8:2839\u20132844. https:\/\/doi.org\/10.1016\/S0960-894X(98)00522-8","journal-title":"Bioorg Med Chem Lett"},{"key":"1799_CR9","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.coph.2006.08.012","volume":"7","author":"J Girault","year":"2007","unstructured":"Girault J, Valjent E, Caboche J, Herve D (2007) ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol 7:77\u201385. https:\/\/doi.org\/10.1016\/j.coph.2006.08.012","journal-title":"Curr Opin Pharmacol"},{"key":"1799_CR10","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1016\/j.bmc.2013.12.040","volume":"22","author":"R Gitto","year":"2014","unstructured":"Gitto R, De Luca L, Ferro S, Russo E, De Sarro G, Chisari M et al (2014) Synthesis, modelling and biological characterization of 3-substituted-1H-indoles as ligands of GluN2B-containing N-methyl-d-aspartate receptors. Bioorg Med Chem 22:1040\u20131048. https:\/\/doi.org\/10.1016\/j.bmc.2013.12.040","journal-title":"Bioorg Med Chem"},{"key":"1799_CR11","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.coph.2003.11.002","volume":"4","author":"P Kalivas","year":"2004","unstructured":"Kalivas P (2004) Glutamate systems in cocaine addiction. Curr Opin Pharmacol 4:23\u201329. https:\/\/doi.org\/10.1016\/j.coph.2003.11.002","journal-title":"Curr Opin Pharmacol"},{"key":"1799_CR12","unstructured":"Kalivas, P. W., and Alesdatter, J. E. (1993). Involvement of N-methyl-D-aspartate receptor stimulation in the ventral tegmental area and amygdala in behavioral sensitization to cocaine. J. Pharmacol. Exp. Ther. 267, 486\u201395. Available at: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/8229779."},{"key":"1799_CR13","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/0165-0173(91)90007-u","volume":"16","author":"PW Kalivas","year":"1991","unstructured":"Kalivas PW, Stewart J (1991) Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity. Brain Res Rev 16:223\u2013244. https:\/\/doi.org\/10.1016\/0165-0173(91)90007-u","journal-title":"Brain Res Rev"},{"key":"1799_CR14","doi-asserted-by":"publisher","first-page":"7921","DOI":"10.1523\/JNEUROSCI.1859-07.2007","volume":"27","author":"S Kourrich","year":"2007","unstructured":"Kourrich S, Rothwell PE, Klug JR, Thomas MJ (2007) Cocaine experience controls bidirectional synaptic plasticity in the nucleus accumbens. J Neurosci 27:7921\u20137928. https:\/\/doi.org\/10.1523\/JNEUROSCI.1859-07.2007","journal-title":"J Neurosci"},{"key":"1799_CR16","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1038\/nn.2103","volume":"11","author":"SE London","year":"2008","unstructured":"London SE, Clayton DF (2008) Functional identification of sensory mechanisms required for developmental song learning. Nat Neurosci 11:579\u2013586. https:\/\/doi.org\/10.1038\/nn.2103","journal-title":"Nat Neurosci"},{"key":"1799_CR17","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1038\/nn1383","volume":"8","author":"L Lu","year":"2005","unstructured":"Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8:212\u2013219. https:\/\/doi.org\/10.1038\/nn1383","journal-title":"Nat Neurosci"},{"key":"1799_CR18","doi-asserted-by":"publisher","first-page":"695","DOI":"10.1016\/j.tins.2006.10.005","volume":"29","author":"L Lu","year":"2006","unstructured":"Lu L, Koya E, Zhai H, Hope BT, Shaham Y (2006) Role of ERK in cocaine addiction. Trends Neurosci 29:695\u2013703. https:\/\/doi.org\/10.1016\/j.tins.2006.10.005","journal-title":"Trends Neurosci"},{"key":"1799_CR19","doi-asserted-by":"publisher","first-page":"844","DOI":"10.1038\/nrn2234","volume":"8","author":"RC Malenka","year":"2007","unstructured":"Malenka RC, Kauer J, a, Malenka, R. C., and Kauer, J. a, (2007) Synaptic plasticity and addiction. Nat Rev Neurosci 8:844\u2013858. https:\/\/doi.org\/10.1038\/nrn2234","journal-title":"Nat Rev Neurosci"},{"key":"1799_CR20","doi-asserted-by":"publisher","first-page":"1481","DOI":"10.1111\/j.1471-4159.2005.03500.x","volume":"95","author":"BJ Mattson","year":"2005","unstructured":"Mattson BJ, Bossert JM, Simmons DE, Nozaki N, Nagarkar D, Kreuter JD et al (2005) Cocaine-induced CREB phosphorylation in nucleus accumbens of cocaine-sensitized rats is enabled by enhanced activation of extracellular signal-related kinase, but not protein kinase A. J Neurochem 95:1481\u20131494. https:\/\/doi.org\/10.1111\/j.1471-4159.2005.03500.x","journal-title":"J Neurochem"},{"key":"1799_CR21","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1016\/j.neuron.2005.08.006","volume":"47","author":"CA Miller","year":"2005","unstructured":"Miller CA, Marshall JF (2005) Molecular substrates for retrieval and reconsolidation of cocaine-associated contextual memory. Neuron 47:873\u2013884. https:\/\/doi.org\/10.1016\/j.neuron.2005.08.006","journal-title":"Neuron"},{"key":"1799_CR22","doi-asserted-by":"crossref","unstructured":"Ortiz, J., Harris, H. W., Guitart, X., Terwilliger, R. Z., Haycock, J. W., and Nestler, E. J. (1995). Extracellular signal-regulated protein kinases (ERKs) and ERK kinase (MEK) in brain: regional distribution and regulation by chronic morphine. J. Neurosci. 15, 1285\u201397. Available at: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/7532701.","DOI":"10.1523\/JNEUROSCI.15-02-01285.1995"},{"key":"1799_CR23","unstructured":"Paxinos, G., and Watson, C. (2007). The Rat Brain in Stereotaxic Coordinates Sixth Edition."},{"key":"1799_CR24","doi-asserted-by":"publisher","first-page":"8685","DOI":"10.1523\/JNEUROSCI.19-19-08685.1999","volume":"19","author":"RC Pierce","year":"1999","unstructured":"Pierce RC, Pierce-Bancroft AF, Prasad BM (1999) Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras\/Mitogen-activated protein kinase signal transduction cascade. J Neurosci 19:8685\u20138695. https:\/\/doi.org\/10.1523\/JNEUROSCI.19-19-08685.1999","journal-title":"J Neurosci"},{"key":"1799_CR26","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.neuroscience.2010.03.034","volume":"168","author":"Z Ren","year":"2010","unstructured":"Ren Z, Sun WL, Jiao H, Zhang D, Kong H, Wang X et al (2010) Dopamine D1 and N-methyl-d-aspartate receptors and extracellular signal-regulated kinase mediate neuronal morphological changes induced by repeated cocaine administration. Neuroscience 168:48\u201360. https:\/\/doi.org\/10.1016\/j.neuroscience.2010.03.034","journal-title":"Neuroscience"},{"key":"1799_CR27","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/0165-0173(93)90013-P","volume":"18","author":"T Robinson","year":"1993","unstructured":"Robinson T (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247\u2013291. https:\/\/doi.org\/10.1016\/0165-0173(93)90013-P","journal-title":"Brain Res Rev"},{"key":"1799_CR30","doi-asserted-by":"publisher","first-page":"6955","DOI":"10.1523\/JNEUROSCI.1329-09.2009","volume":"29","author":"J Schumann","year":"2009","unstructured":"Schumann J, Yaka R (2009) Prolonged withdrawal from repeated noncontingent cocaine exposure increases NMDA receptor expression and ERK activity in the nucleus accumbens. J Neurosci 29:6955\u20136963. https:\/\/doi.org\/10.1523\/JNEUROSCI.1329-09.2009","journal-title":"J Neurosci"},{"key":"1799_CR32","doi-asserted-by":"publisher","unstructured":"Sun, W.-L., Quizon, P. M., and Zhu, J. (2016). \u201cMolecular Mechanism: ERK Signaling, Drug Addiction, and Behavioral Effects,\u201d in, 1\u201340. https:\/\/doi.org\/10.1016\/bs.pmbts.2015.10.017.","DOI":"10.1016\/bs.pmbts.2015.10.017"},{"key":"1799_CR33","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/bjp.2008.77","volume":"154","author":"MJ Thomas","year":"2008","unstructured":"Thomas MJ, Kalivas PW, Shaham Y (2008) Neuroplasticity in the mesolimbic dopamine system and cocaine addiction. Br J Pharmacol 154:327\u2013342. https:\/\/doi.org\/10.1038\/bjp.2008.77","journal-title":"Br J Pharmacol"},{"key":"1799_CR34","doi-asserted-by":"publisher","first-page":"8701","DOI":"10.1523\/JNEUROSCI.20-23-08701.2000","volume":"20","author":"E Valjent","year":"2000","unstructured":"Valjent E, Corvol J-C, Pag\u00e8s C, Besson M-J, Maldonado R, Caboche J (2000) Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 20:8701\u20138709. https:\/\/doi.org\/10.1523\/JNEUROSCI.20-23-08701.2000","journal-title":"J Neurosci"},{"key":"1799_CR35","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/1471-2202-7-20","volume":"7","author":"E Valjent","year":"2006","unstructured":"Valjent E, Corvol J-C, Trzaskos JM, Girault J-A, Herv\u00e9 D (2006) Role of the ERK pathway in psychostimulant-induced locomotor sensitization. BMC Neurosci 7:20. https:\/\/doi.org\/10.1186\/1471-2202-7-20","journal-title":"BMC Neurosci"},{"key":"1799_CR36","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1111\/j.1460-9568.2004.03278.x","volume":"19","author":"E Valjent","year":"2004","unstructured":"Valjent E, Pages C, Herve D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826\u20131836. https:\/\/doi.org\/10.1111\/j.1460-9568.2004.03278.x","journal-title":"Eur J Neurosci"},{"key":"1799_CR37","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1073\/pnas.0408305102","volume":"102","author":"E Valjent","year":"2005","unstructured":"Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol J-C et al (2005) From the cover: regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc Natl Acad Sci 102:491\u2013496. https:\/\/doi.org\/10.1073\/pnas.0408305102","journal-title":"Proc Natl Acad Sci"},{"key":"1799_CR38","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/s0301-0082(97)00090-7","volume":"54","author":"ME Wolf","year":"1998","unstructured":"Wolf ME (1998) The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants. Prog Neurobiol 54:679\u2013720. https:\/\/doi.org\/10.1016\/s0301-0082(97)00090-7","journal-title":"Prog Neurobiol"},{"key":"1799_CR39","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1007\/s10571-007-9240-3","volume":"28","author":"H Zhai","year":"2008","unstructured":"Zhai H, Li Y, Wang X, Lu L (2008) Drug-induced alterations in the extracellular signal-regulated kinase (ERK) signalling pathway: implications for reinforcement and reinstatement. Cell Mol Neurobiol 28:157\u2013172. https:\/\/doi.org\/10.1007\/s10571-007-9240-3","journal-title":"Cell Mol Neurobiol"},{"key":"1799_CR40","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/S0092-8674(02)00897-8","volume":"110","author":"JJ Zhu","year":"2002","unstructured":"Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110:443\u2013455. https:\/\/doi.org\/10.1016\/S0092-8674(02)00897-8","journal-title":"Cell"}],"container-title":["Journal of Molecular Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12031-021-01799-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12031-021-01799-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12031-021-01799-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T00:16:44Z","timestamp":1636676204000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12031-021-01799-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,21]]},"references-count":35,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["1799"],"URL":"https:\/\/doi.org\/10.1007\/s12031-021-01799-6","relation":{},"ISSN":["0895-8696","1559-1166"],"issn-type":[{"value":"0895-8696","type":"print"},{"value":"1559-1166","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,21]]},"assertion":[{"value":"10 December 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. Animal use and care were endorsed by the animal management committee of the Hebrew University of Jerusalem.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}}]}}