{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T10:21:59Z","timestamp":1774952519041,"version":"3.50.1"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T00:00:00Z","timestamp":1667433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The nucleus accumbens (NAc) is involved in the expression of cocaine addictive phenotypes, including acquisition, extinction, and reinstatement. In the NAc, D1-medium spiny neurons (MSNs) encode cocaine reward, whereas D2-MSNs encode aversive responses in drug addiction. Glutamate receptor-interacting protein 1 (GRIP1) is known to be associated with cocaine addiction, but the role of GRIP1 in D1-MSNs and D2-MSNs of the NAc in cocaine acquisition and reinstatement remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A conditioned place preference apparatus was used to establish cocaine acquisition, extinction, and reinstatement in mouse models. GRIP1 expression was evaluated using Western blotting. Furthermore, GRIP1-siRNA and GRIP1 overexpression lentivirus were used to interfere with GRIP1 in the NAc. After the behavioral test, green fluorescent protein immunostaining of brain slices was used to detect spine density.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>GRIP1 expression decreased during cocaine acquisition and reinstatement. GRIP1-siRNA enhanced cocaine-induced CPP behavior in acquisition and reinstatement and regulated associated spine plasticity. Importantly, the decreased GRIP1 expression that mediated cocaine acquisition and reinstatement was mainly driven by the interference of the GRIP1-GluA2 interaction in D1-MSNs and could be blocked by the interference of the GRIP1-GluA2 interaction in D2-MSNs. Interference with the GRIP1-GluA2 interaction in D1- and D2-MSNs decreased spine density in D1- and D2-MSNs, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>GRIP1 in D1- and D2-MSNs of the NAc differentially modulates cocaine acquisition and reinstatement. GRIP1 downregulation in D1-MSNs has a positive effect on cocaine acquisition and reinstatement, while GRIP1 downregulation in D2-MSNs has a negative effect. Additionally, GRIP1 downregulation in D1-MSNs plays a leading role in cocaine acquisition and reinstatement.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncel.2022.979078","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T08:02:22Z","timestamp":1667462542000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Glutamate receptor-interacting protein 1 in D1- and D2-dopamine receptor-expressing medium spiny neurons differentially regulates cocaine acquisition, reinstatement, and associated spine plasticity"],"prefix":"10.3389","volume":"16","author":[{"given":"He","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Limei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhirong","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiajie","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yitong","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuesi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jieyi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guohua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aav1483","article-title":"Synaptotagmin-3 drives AMPA receptor endocytosis, depression of synapse strength, and forgetting.","volume":"363","author":"Awasthi","year":"2019","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.biopsych.2018.04.019","article-title":"Cocaine-induced structural plasticity in input regions to distinct cell types in nucleus accumbens.","volume":"84","author":"Barrientos","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4785","DOI":"10.1523\/JNEUROSCI.3020-17.2019","article-title":"Synaptic depotentiation and mGluR5 activity in the nucleus accumbens drive cocaine-primed reinstatement of place preference.","volume":"39","author":"Benneyworth","year":"2019","journal-title":"J. Neurosci."},{"key":"B4","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1016\/j.brainresbull.2010.09.003","article-title":"Influence of sex on reinstatement of cocaine-conditioned place preference.","volume":"83","author":"Bobzean","year":"2010","journal-title":"Brain Res. Bull."},{"key":"B5","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.conb.2007.04.009","article-title":"Do thin spines learn to be mushroom spines that remember?","volume":"17","author":"Bourne","year":"2007","journal-title":"Curr. Opin. Neurobiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"759","DOI":"10.1038\/npp.2013.265","article-title":"Disruption of glutamate receptor-interacting protein in nucleus accumbens enhances vulnerability to cocaine relapse.","volume":"39","author":"Briand","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"7516","DOI":"10.1523\/JNEUROSCI.0600-18.2018","article-title":"Dnmt3a2 in the nucleus accumbens shell is required for reinstatement of cocaine seeking.","volume":"38","author":"Cannella","year":"2018","journal-title":"J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1395","DOI":"10.1073\/pnas.1621185114","article-title":"WAVE1 in neurons expressing the D1 dopamine receptor regulates cellular and behavioral actions of cocaine.","volume":"114","author":"Ceglia","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B9","doi-asserted-by":"publisher","first-page":"7927","DOI":"10.1523\/JNEUROSCI.0548-15.2015","article-title":"Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action.","volume":"35","author":"Chandra","year":"2015","journal-title":"J. Neurosci."},{"key":"B10","doi-asserted-by":"crossref","first-page":"7258","DOI":"10.1523\/JNEUROSCI.20-19-07258.2000","article-title":"Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins.","volume":"20","author":"Chung","year":"2000","journal-title":"J. Neurosci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1016\/j.conb.2006.05.012","article-title":"Regulation of Ca2+-permeable AMPA receptors: Synaptic plasticity and beyond.","volume":"16","author":"Cull-Candy","year":"2006","journal-title":"Curr. Opin. Neurobiol."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/1756-6606-2-18","article-title":"A novel mechanism of hippocampal LTD involving muscarinic receptor-triggered interactions between AMPARs. GRIP and liprin-alpha.","volume":"2","author":"Dickinson","year":"2009","journal-title":"Mol. Brain"},{"key":"B13","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/386279a0","article-title":"GRIP: A synaptic PDZ domain-containing protein that interacts with AMPA receptors.","volume":"386","author":"Dong","year":"1997","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"crossref","first-page":"6930","DOI":"10.1523\/JNEUROSCI.19-16-06930.1999","article-title":"Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2.","volume":"19","author":"Dong","year":"1999","journal-title":"J. Neurosci."},{"key":"B15","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1113\/jphysiol.2014.273755","article-title":"Assembly of AMPA receptors: Mechanisms and regulation.","volume":"593","author":"Gan","year":"2015","journal-title":"J. Physiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/0896-6273(95)90076-4","article-title":"Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS.","volume":"15","author":"Geiger","year":"1995","journal-title":"Neuron"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5030","DOI":"10.1073\/pnas.1304301111","article-title":"GRIP1 interlinks N-cadherin and AMPA receptors at vesicles to promote combined cargo transport into dendrites.","volume":"111","author":"Heisler","year":"2014","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/j.neuron.2010.05.011","article-title":"Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior.","volume":"66","author":"Hikida","year":"2010","journal-title":"Neuron"},{"key":"B19","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.neuron.2009.06.007","article-title":"In vivo cocaine experience generates silent synapses.","volume":"63","author":"Huang","year":"2009","journal-title":"Neuron"},{"key":"B20","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1016\/j.bbr.2013.08.009","article-title":"Opioid self-administration results in cell-type specific adaptations of striatal medium spiny neurons.","volume":"256","author":"James","year":"2013","journal-title":"Behav. Brain Res."},{"key":"B21","author":"Kennedy","year":"2016","journal-title":"A Dual Investigation of Questions in Drug Addiction: Exploring the Role of Neuroinflammation in Opioid Withdrawal and A Novel Measure of Reward-Seeking Behavior in Rodents."},{"key":"B22","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1016\/j.biopsych.2015.05.022","article-title":"Stress and cocaine trigger divergent and cell type-specific regulation of synaptic transmission at single spines in nucleus accumbens.","volume":"79","author":"Khibnik","year":"2016","journal-title":"Biological psychiatry"},{"key":"B23","doi-asserted-by":"publisher","first-page":"11725","DOI":"10.1073\/pnas.211132798","article-title":"Interaction of the AMPA receptor subunit GluR2\/3 with PDZ domains regulates hippocampal long-term depression.","volume":"98","author":"Kim","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B24","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.biopsych.2011.01.013","article-title":"Cell type-specific alterations in the nucleus accumbens by repeated exposures to cocaine.","volume":"69","author":"Kim","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"B25","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/nn.3100","article-title":"Distinct roles for direct and indirect pathway striatal neurons in reinforcement.","volume":"15","author":"Kravitz","year":"2012","journal-title":"Nat. Neurosci."},{"key":"B26","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1523\/JNEUROSCI.2584-18.2019","article-title":"Dnmt3a2 in the nucleus accumbens shell mediates cue-induced cocaine-seeking behavior.","volume":"39","author":"Lax","year":"2019","journal-title":"J. Neurosci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1038\/nn.3533","article-title":"Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving.","volume":"16","author":"Lee","year":"2013","journal-title":"Nat. Neurosci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"3399","DOI":"10.1073\/pnas.0511244103","article-title":"Cocaine-induced dendritic spine formation in D1 and D2 dopamine receptor-containing medium spiny neurons in nucleus accumbens.","volume":"103","author":"Lee","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B29","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/cne.20566","article-title":"GRIP1 in GABAergic synapses.","volume":"488","author":"Li","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"8938","DOI":"10.1523\/JNEUROSCI.0703-17.2017","article-title":"Calpain-GRIP signaling in nucleus accumbens core mediates the reconsolidation of drug reward memory.","volume":"37","author":"Liang","year":"2017","journal-title":"J. Neurosci."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-018-0273-9","article-title":"Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens.","volume":"8","author":"Liu","year":"2018","journal-title":"Trans. Psychiatry"},{"key":"B32","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1126\/science.1188472","article-title":"Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward.","volume":"330","author":"Lobo","year":"2010","journal-title":"Science"},{"key":"B33","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.neuron.2005.07.006","article-title":"PICK1 interacts with ABP\/GRIP to regulate AMPA receptor trafficking.","volume":"47","author":"Lu","year":"2005","journal-title":"Neuron"},{"key":"B34","doi-asserted-by":"publisher","first-page":"6819","DOI":"10.1074\/jbc.M111.293365","article-title":"Receptor tyrosine kinase Ephb6 regulates vascular smooth muscle contractility and modulates blood pressure in concert with sex hormones.","volume":"287","author":"Luo","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1016\/j.neuron.2011.01.017","article-title":"Drug-evoked synaptic plasticity in addiction: From molecular changes to circuit remodeling.","volume":"69","author":"L\u00fcscher","year":"2011","journal-title":"Neuron"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2311","DOI":"10.1007\/s00429-019-01903-y","article-title":"Cell-type and region-specific nucleus accumbens AMPAR plasticity associated with morphine reward, reinstatement, and spontaneous withdrawal.","volume":"224","author":"Madayag","year":"2019","journal-title":"Brain Structure Funct."},{"key":"B37","doi-asserted-by":"publisher","first-page":"19038","DOI":"10.1073\/pnas.1013494107","article-title":"GRIP1 and 2 regulate activity-dependent AMPA receptor recycling via exocyst complex interactions.","volume":"107","author":"Mao","year":"2010","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1038\/nn736","article-title":"Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons.","volume":"4","author":"Matsuzaki","year":"2001","journal-title":"Nat. Neurosci."},{"key":"B39","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/nature13294","article-title":"Engineering a memory with LTD and LTP.","volume":"511","author":"Nabavi","year":"2014","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.2147\/NDT.S45963","article-title":"Role of nucleus accumbens glutamatergic plasticity in drug addiction.","volume":"9","author":"Quintero","year":"2013","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"B41","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1038\/s41380-019-0484-3","article-title":"Nucleus accumbens medium spiny neurons subtypes signal both reward and aversion.","volume":"25","author":"Soares-Cunha","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"B42","doi-asserted-by":"publisher","first-page":"5752","DOI":"10.1523\/JNEUROSCI.0654-08.2008","article-title":"The glutamate receptor-interacting protein family of GluR2-binding proteins is required for long-term synaptic depression expression in cerebellar Purkinje cells.","volume":"28","author":"Takamiya","year":"2008","journal-title":"J. Neurosci."},{"key":"B43","doi-asserted-by":"crossref","first-page":"25085","DOI":"10.1073\/pnas.2014827117","article-title":"GRIP1 regulates synaptic plasticity and learning and memory.","volume":"117","author":"Tan","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1779","DOI":"10.1038\/npp.2015.345","article-title":"Cell-Type Specific Insertion of GluA2-Lacking AMPARs with Cocaine Exposure Leading to Sensitization, Cue-Induced Seeking, and Incubation of Craving.","volume":"41","author":"Terrier","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"B45","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.neuroscience.2022.07.009","article-title":"Glutamate receptor interacting protein 1 in the dorsal ca1 drives alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor endocytosis and exocytosis bidirectionally and mediates forgetting. exploratory, and anxiety-like behavior.","volume":"498","author":"Wang","year":"2022","journal-title":"Neuroscience"},{"key":"B46","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1016\/j.biopsych.2016.04.020","article-title":"BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior.","volume":"80","author":"Wang","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"B47","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1038\/npp.2015.199","article-title":"A critical role for the GluA1 accessory protein, SAP97, in cocaine seeking.","volume":"41","author":"White","year":"2016","journal-title":"Neuropsychopharmacology"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107672","article-title":"Glutamate receptor interacting protein acts within the prefrontal cortex to blunt cocaine seeking.","volume":"157","author":"Wickens","year":"2019","journal-title":"Neuropharmacology"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13588","article-title":"Regulation of Cdc42 signaling by the dopamine D2 receptor in a mouse model of Parkinson\u2019s disease.","volume":"21","author":"Ying","year":"2022","journal-title":"Aging Cell"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2020.558074","article-title":"The projection from ventral CA1. not prefrontal cortex, to nucleus accumbens core mediates recent memory retrieval of cocaine-conditioned place preference.","volume":"14","author":"Zhou","year":"2020","journal-title":"Front. Behav. Neurosci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1986","DOI":"10.1038\/s41593-019-0524-y","article-title":"A ventral CA1 to nucleus accumbens core engram circuit mediates conditioned place preference for cocaine.","volume":"22","author":"Zhou","year":"2019","journal-title":"Nat. Neurosci."}],"container-title":["Frontiers in Cellular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.979078\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T08:02:37Z","timestamp":1667462557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncel.2022.979078\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,3]]},"references-count":51,"alternative-id":["10.3389\/fncel.2022.979078"],"URL":"https:\/\/doi.org\/10.3389\/fncel.2022.979078","relation":{},"ISSN":["1662-5102"],"issn-type":[{"value":"1662-5102","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,3]]},"article-number":"979078"}}