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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,5,5]]},"abstract":"<jats:p>\n                    The initial response to an addictive substance can facilitate repeated use: That is, individuals experiencing more positive effects are more likely to use that drug again. Increasing evidence suggests that psychoactive cannabinoid use in adolescence enhances the behavioral effects of cocaine. However, despite the behavioral data, there is no neurobiological evidence demonstrating that cannabinoids can also alter the brain\u2019s initial molecular and epigenetic response to cocaine. Here, we utilized a multiomics approach (epigenomics, transcriptomics, proteomics, and phosphoproteomics) to characterize how the rat brain responds to its first encounter with cocaine, with or without preexposure to the synthetic cannabinoid WIN 55,212-2 (WIN). We find that in adolescent (but not in adult) rats, preexposure to WIN results in cross-sensitization to cocaine, which correlates with histone hyperacetylation and decreased levels of HDAC6 in the prefrontal cortex (PFC). In the PFC, we also find that WIN preexposure blunts the typical mRNA response to cocaine and instead results in alternative splicing and chromatin accessibility events, involving genes such as\n                    <jats:italic>Npas2<\/jats:italic>\n                    . Moreover, preexposure to WIN enhances the effects of cocaine on protein phosphorylation, including ERK\/MAPK-targets like gephyrin, and modulates the synaptic AMPAR\/GluR composition both in the PFC and the nucleus accumbens (NAcc). PFC\u2013NAcc gene network topological analyses, following cocaine exposure, reveal distinct top nodes in the WIN preexposed group, which include PACAP\/ADCYAP1. These preclinical data demonstrate that adolescent cannabinoid exposure reprograms the initial behavioral, molecular, and epigenetic response to cocaine.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1920866117","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T20:27:01Z","timestamp":1587414421000},"page":"9991-10002","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":49,"title":["Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine"],"prefix":"10.1073","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8652-9594","authenticated-orcid":false,"given":"Maria","family":"Scherma","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna S.","family":"Qvist","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Columbia University, New York, NY 10032;"},{"name":"Jerome L. Greene Science Center, Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY 10027;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9056-8799","authenticated-orcid":false,"given":"Arun","family":"Asok","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Columbia University, New York, NY 10032;"},{"name":"Jerome L. Greene Science Center, Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY 10027;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-shan C.","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Genomics and Systems Biology, Department of Biology, New York University, New York, NY 10003;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Masia","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Deidda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya B.","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of California San Diego, La Jolla, CA 92093;"},{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, 17176 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh K.","family":"Soni","sequence":"additional","affiliation":[{"name":"Proteomics Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Fratta","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Fadda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Cagliari, Italy;"},{"name":"Neuroscience Institute, National Research Council of Italy (CNR), 09042 Cagliari, Italy;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7851-6902","authenticated-orcid":false,"given":"Eric R.","family":"Kandel","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Columbia University, New York, NY 10032;"},{"name":"Jerome L. Greene Science Center, Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY 10027;"},{"name":"Kavli Institute for Brain Science, Columbia University, New York, NY 10032;"},{"name":"Howard Hughes Medical Institute, Chevy Chase, MD 20815;"},{"name":"New York State Psychiatric Institute, New York, NY 10032;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0458-6961","authenticated-orcid":false,"given":"Denise B.","family":"Kandel","sequence":"additional","affiliation":[{"name":"New York State Psychiatric Institute, New York, NY 10032;"},{"name":"Department of Psychiatry, Vagelos College of Physicians and Surgeons and Mailman School of Public Health, Columbia University, New York, NY 10032;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7889-9250","authenticated-orcid":false,"given":"Philippe A.","family":"Melas","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Columbia University, New York, NY 10032;"},{"name":"Jerome L. Greene Science Center, Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY 10027;"},{"name":"Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden;"},{"name":"Center for Psychiatry Research, Karolinska Institutet, 17176 Stockholm, Sweden;"},{"name":"Center for Molecular Medicine, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2020,4,20]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/npp.2017.143","article-title":"The role of the endocannabinoid system and genetic variation in adolescent brain development","volume":"43","author":"Meyer H. C.","year":"2018","unstructured":"H. C. Meyer, F. S. Lee, D. G. Gee, The role of the endocannabinoid system and genetic variation in adolescent brain development. 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Melas ., Cannabinoid modulation of eukaryotic initiation factors (eIF2\u03b1 and eIF2B1) and behavioral cross-sensitization to cocaine in adolescent rats. Cell Rep. 22, 2909\u20132923 (2018).","journal-title":"Cell Rep."},{"key":"e_1_3_4_14_2","doi-asserted-by":"crossref","first-page":"13893","DOI":"10.1038\/s41598-018-31921-5","article-title":"Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood","volume":"8","author":"Kononoff J.","year":"2018","unstructured":"J. Kononoff ., Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood. Sci. Rep. 8, 13893 (2018).","journal-title":"Sci. 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Higuera-Matas ., Augmented acquisition of cocaine self-administration and altered brain glucose metabolism in adult female but not male rats exposed to a cannabinoid agonist during adolescence. Neuropsychopharmacology 33, 806\u2013813 (2008).","journal-title":"Neuropsychopharmacology"},{"key":"e_1_3_4_17_2","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1037\/pha0000276","article-title":"Effects of adolescent \u03949-tetrahydrocannabinol exposure on the behavioral effects of cocaine in adult Sprague-Dawley rats","volume":"27","author":"Friedman A. L.","year":"2019","unstructured":"A. L. Friedman, C. Meurice, E. M. Jutkiewicz, Effects of adolescent \u03949-tetrahydrocannabinol exposure on the behavioral effects of cocaine in adult Sprague-Dawley rats. Exp. Clin. Psychopharmacol. 27, 326\u2013337 (2019).","journal-title":"Exp. Clin. 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