{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:40:23Z","timestamp":1760143223248,"version":"build-2065373602"},"reference-count":74,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,21]],"date-time":"2024-01-21T00:00:00Z","timestamp":1705795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20K07978","JP23K07044"],"award-info":[{"award-number":["JP20K07978","JP23K07044"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The \u03b4 opioid receptor (DOR) inverse agonist has been demonstrated to improve learning and memory impairment in mice subjected to restraint stress. Here, we investigated the effects of SYK-623, a new DOR inverse agonist, on behavioral, immunohistochemical, and biochemical abnormalities in a mouse model of imipramine treatment-resistant depression. Male ddY mice received daily treatment of adrenocorticotropic hormone (ACTH) combined with chronic mild stress exposure (ACMS). SYK-623, imipramine, or the vehicle was administered once daily before ACMS. After three weeks, ACMS mice showed impaired learning and memory in the Y-maze test and increased immobility time in the forced swim test. SYK-623, but not imipramine, significantly suppressed behavioral abnormalities caused by ACMS. Based on the fluorescent immunohistochemical analysis of the hippocampus, ACMS induced a reduction in astrocytes and newborn neurons, similar to the reported findings observed in the postmortem brains of depressed patients. In addition, the number of parvalbumin-positive GABA neurons, which play a crucial role in neurogenesis, was reduced in the hippocampus, and western blot analysis showed decreased glutamic acid decarboxylase protein levels. These changes, except for the decrease in astrocytes, were suppressed by SYK-623. Thus, SYK-623 mitigates behavioral abnormalities and disturbed neurogenesis caused by chronic stress.<\/jats:p>","DOI":"10.3390\/jcm13020608","type":"journal-article","created":{"date-parts":[[2024,1,22]],"date-time":"2024-01-22T11:36:41Z","timestamp":1705923401000},"page":"608","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SYK-623, a \u03b4 Opioid Receptor Inverse Agonist, Mitigates Chronic Stress-Induced Behavioral Abnormalities and Disrupted Neurogenesis"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1398-3152","authenticated-orcid":false,"given":"Takashi","family":"Iwai","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rei","family":"Mishima","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8293-2236","authenticated-orcid":false,"given":"Shigeto","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Honoka","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misa","family":"Oyama","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shun","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0049-0084","authenticated-orcid":false,"given":"Hideaki","family":"Fujii","sequence":"additional","affiliation":[{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuo","family":"Tanabe","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"},{"name":"Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.ibror.2018.04.001","article-title":"How could stress lead to major depressive disorder?","volume":"4","author":"Xu","year":"2018","journal-title":"IBRO Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9328","DOI":"10.1523\/JNEUROSCI.2281-05.2005","article-title":"Mechanisms of late-onset cognitive decline after early-life stress","volume":"25","author":"Brunson","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.bandc.2007.02.007","article-title":"The effects of stress and stress hormones on human cognition: Implications for the field of brain and cognition","volume":"65","author":"Lupien","year":"2007","journal-title":"Brain Cogn."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e231860","DOI":"10.1001\/jamanetworkopen.2023.1860","article-title":"Association of stress with cognitive function among older black and white US adults","volume":"6","author":"Kulshreshtha","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2750","DOI":"10.1038\/s41380-023-01986-4","article-title":"Neurocognitive effects of stress: A metaparadigm perspective","volume":"28","author":"Kim","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s00213-021-05982-w","article-title":"Chronic mild stress paradigm as a rat model of depression: Facts, artifacts, and future perspectives","volume":"239","author":"Strekalova","year":"2022","journal-title":"Psychopharmacology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1093\/ijnp\/pyx070","article-title":"A network meta-analysis comparing effects of various antidepressant classes on the Digit Symbol Substitution Test (DSST) as a measure of cognitive dysfunction in patients with major depressive disorder","volume":"21","author":"Baune","year":"2018","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1016\/j.neuropharm.2009.06.010","article-title":"Curcumin reverses impaired cognition and neuronal plasticity induced by chronic stress","volume":"57","author":"Xu","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.pbb.2006.01.004","article-title":"Impairment of the spatial learning and memory induced by learned helplessness and chronic mild stress","volume":"83","author":"Song","year":"2006","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00213-007-1035-1","article-title":"Long-lasting behavioral effects and recognition memory deficit induced by chronic mild stress in mice: Effect of antidepressant treatment","volume":"199","author":"Elizalde","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1017\/S1461145706006705","article-title":"Modification of spatial recognition memory and object discrimination after chronic administration of haloperidol, amitriptyline, sodium valproate or olanzapine in normal and anhedonic rats","volume":"10","author":"Orsetti","year":"2007","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s00429-014-0717-9","article-title":"A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks","volume":"220","author":"Erbs","year":"2015","journal-title":"Brain Struct. Funct."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"231","DOI":"10.2174\/157015912803217314","article-title":"Antidepressant-like effects of \u03b4 opioid receptor agonists in animal models","volume":"10","author":"Saitoh","year":"2012","journal-title":"Curr. Neuropharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/sj.bjp.0706686","article-title":"Delta opioid receptor ligands modulate anxiety-like behaviors in the rat","volume":"147","author":"Perrine","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1006\/pupt.2002.0350","article-title":"Delta-opioid receptor antagonists as a new concept for central acting antitussive drugs","volume":"15","author":"Kamei","year":"2002","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1021\/acschemneuro.9b00067","article-title":"Discovery of \u03b4 opioid receptor full inverse agonists and their effects on restraint stress-induced cognitive impairment in mice","volume":"10","author":"Hirayama","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.1021\/acschemneuro.9b00368","article-title":"Development of novel \u03b4 opioid receptor inverse agonists without a basic nitrogen atom and their antitussive effects in mice","volume":"10","author":"Higashi","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1093\/ijnp\/pyy071","article-title":"Making Sense of Pharmacology: Inverse agonism and functional selectivity","volume":"21","author":"Berg","year":"2018","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Iwai, T., Okonogi, T., Mishima, R., Yoshida, K., Oyama, M., Watanabe, S., Hirayama, S., Fujii, H., and Tanabe, M. (2018, January 1\u20136). \u03b4-Opioid receptor inverse agonist SYK-623 improved stress-induced learning dysfunction in mice. Proceedings of the Annual Meeting of The Japanese Pharmacological Society WCP2018 (The 18th World Congress of Basic and Clinical Pharmacology), Kyoto, Japan.","DOI":"10.1254\/jpssuppl.WCP2018.0_PO1-1-20"},{"key":"ref_20","first-page":"219","article-title":"Effects of imipramine and lithium on the suppression of cell proliferation in the dentate gyrus of the hippocampus in adrenocorticotropic hormone-treated rats","volume":"64","author":"Doi","year":"2010","journal-title":"Acta Med. Okayama"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.bbr.2013.01.010","article-title":"Glucagon-like peptide-2 but not imipramine exhibits antidepressant-like effects in ACTH-treated mice","volume":"243","author":"Iwai","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1016\/j.biopsych.2013.03.032","article-title":"From pathophysiology to novel antidepressant drugs: Glial contributions to the pathology and treatment of mood disorders","volume":"73","author":"Sanacora","year":"2013","journal-title":"Biol. Psychiatry"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Darcet, F., Gardier, A.M., Gaillard, R., David, D.J., and Guilloux, J.-P. (2016). Cognitive dysfunction in major depressive disorder. A translational review in animal models of the disease. Pharmaceuticals, 9.","DOI":"10.3390\/ph9010009"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.bbi.2021.09.013","article-title":"Defects of parvalbumin-positive interneurons in the ventral dentate gyrus region are implicated depression-like behavior in mice","volume":"99","author":"Chen","year":"2022","journal-title":"Brain Behav. Immun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ynstr.2016.08.001","article-title":"Reliability of the chronic mild stress model of depression: A user survey","volume":"6","author":"Willner","year":"2017","journal-title":"Neurobiol. Stress"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.bbr.2009.06.020","article-title":"Antidepressant-like effects of glucagon-like peptide-2 in mice occur via monoamine pathways","volume":"204","author":"Iwai","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"112506","DOI":"10.1016\/j.bbr.2020.112506","article-title":"Mirogabalin prevents repeated restraint stress-induced dysfunction in mice","volume":"383","author":"Iwai","year":"2020","journal-title":"Behav. Brain Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zhao, Q., Niu, Y., Matsumoto, K., Tsuneyama, K., Tanaka, K., Miyata, T., and Yokozawa, T. (2012). Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: Possible Involvement of cholinergic and VEGF\/PDGF mechanisms in the brain. BMC Complement Altern. Med., 12.","DOI":"10.1186\/1472-6882-12-188"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1038\/nprot.2013.155","article-title":"Object recognition test in mice","volume":"8","author":"Leger","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1111\/j.1440-1681.1998.tb02179.x","article-title":"Multiple Comparison Procedures Updated","volume":"25","author":"Ludbrook","year":"1998","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"E965","DOI":"10.1152\/ajpendo.00070.2006","article-title":"Chronic stress induces adrenal hyperplasia and hypertrophy in a subregion-specific manner","volume":"291","author":"Figueiredo","year":"2006","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Machado-Santos, A.R., Loureiro-Campos, E., Patr\u00edcio, P., Ara\u00fajo, B., Alves, N.D., Mateus-Pinheiro, A., Correia, J.S., Morais, M., Bessa, J.M., and Sousa, N. (2022). Beyond new neurons in the adult hippocampus: Imipramine acts as a pro-astrogliogenic factor and rescues cognitive impairments induced by stress exposure. Cells, 11.","DOI":"10.3390\/cells11030390"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1002\/dneu.22014","article-title":"Modification of hippocampal circuitry by adult neurogenesis","volume":"72","author":"Song","year":"2012","journal-title":"Dev. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"680903","DOI":"10.3389\/fphar.2021.680903","article-title":"Ginsenoside Rb1 produces antidepressant-like effects in a chronic social defeat stress model of depression through the BDNF-TrkB signaling pathway","volume":"12","author":"Jiang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101655","DOI":"10.1016\/j.jchemneu.2019.101655","article-title":"A single injection of imipramine affected proliferation in the hippocampus of adult swiss mice depending on the route of administration, doses, survival time and lodging conditions","volume":"100","author":"Podolan","year":"2019","journal-title":"J. Chem. Neuroanat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1111\/j.1460-9568.2011.07668.x","article-title":"Reduction in hippocampal neurogenesis after social defeat is long-lasting and responsive to late antidepressant treatment: Lasting effect of social stress on neurogenesis","volume":"33","author":"Oomen","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/s41398-019-0603-6","article-title":"Region specific knockdown of parvalbumin or somatostatin produces neuronal and behavioral deficits consistent with those observed in schizophrenia","volume":"9","author":"Perez","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Perlman, G., Tanti, A., and Mechawar, N. (2021). Parvalbumin interneuron alterations in stress-related mood disorders: A systematic review. Neurobiol. Stress, 15.","DOI":"10.1016\/j.ynstr.2021.100380"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1042\/EBC20220091","article-title":"Astrocytes in memory formation and maintenance","volume":"67","author":"Bohmbach","year":"2023","journal-title":"Essays Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"E3343","DOI":"10.1073\/pnas.1410893111","article-title":"Astrocytes contribute to gamma oscillations and recognition memory","volume":"111","author":"Lee","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.nlm.2013.07.011","article-title":"Role of adult neurogenesis in hippocampus-dependent memory, contextual fear extinction and remote contextual memory: New insights from ERK5 MAP kinase","volume":"105","author":"Pan","year":"2013","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1097\/FBP.0b013e3282ee2aa8","article-title":"The role of neurotrophic factors in adult hippocampal neurogenesis, antidepressant treatments and animal models of depressive-like behavior","volume":"18","author":"Schmidt","year":"2007","journal-title":"Behav. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/j.bbr.2012.10.024","article-title":"Effects of chronic treatment with corticosterone and imipramine on Fos immunoreactivity and adult hippocampal neurogenesis","volume":"238","author":"Diniz","year":"2013","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.1083328","article-title":"Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants","volume":"301","author":"Santarelli","year":"2003","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.biopsych.2008.02.022","article-title":"Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversal","volume":"64","author":"Surget","year":"2008","journal-title":"Biol. Psychiatry"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.neuron.2009.04.017","article-title":"Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety\/depression","volume":"62","author":"David","year":"2009","journal-title":"Neuron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1248\/bpb.34.77","article-title":"Chronic treatment with imipramine and lithium increases cell proliferation in the hippocampus in adrenocorticotropic hormone-treated rats","volume":"34","author":"Kitamura","year":"2011","journal-title":"Biol. Pharm. Bull."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S0091-3057(01)00769-9","article-title":"Effects of imipramine and lithium on wet-dog shakes mediated by the 5-HT2A receptor in ACTH-treated rats","volume":"72","author":"Kitamura","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_50","first-page":"14","article-title":"Oppositional Effects of Serotonin Receptors 5-HT1a, 2, and 2c in the Regulation of Adult Hippocampal Neurogenesis","volume":"3","author":"Klempin","year":"2010","journal-title":"Front. Mol. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.neuroscience.2012.06.023","article-title":"Distribution of delta opioid receptor-expressing neurons in the mouse hippocampus","volume":"221","author":"Erbs","year":"2012","journal-title":"Neuroscience"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.neuron.2010.09.017","article-title":"NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory","volume":"68","author":"Korotkova","year":"2010","journal-title":"Neuron"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1093\/cercor\/bhq017","article-title":"Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus","volume":"20","author":"Morellini","year":"2010","journal-title":"Cereb. Cortex"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/s00441-017-2668-y","article-title":"Neural mechanisms underlying GABAergic regulation of adult hippocampal neurogenesis","volume":"371","author":"Catavero","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1038\/nn.3572","article-title":"Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus","volume":"16","author":"Song","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neuroscience.2008.11.054","article-title":"Inhibition of adult hippocampal neurogenesis disrupts contextual learning but spares spatial working memory, long-term conditional rule retention and spatial reversal","volume":"159","author":"Ferragud","year":"2009","journal-title":"Neuroscience"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1073\/pnas.0611718104","article-title":"Paradoxical influence of hippocampal neurogenesis on working memory","volume":"104","author":"Saxe","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e1058","DOI":"10.1038\/tp.2017.29","article-title":"Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression","volume":"7","author":"Alves","year":"2017","journal-title":"Transl. Psychiatry"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Foyet, H.S., Tchinda Deffo, S., Koagne Yewo, P., Antioch, I., Zingue, S., Asongalem, E.A., Kamtchouing, P., and Ciobica, A. (2017). Ficus sycomorus extract reversed behavioral impairment and brain oxidative stress induced by unpredictable chronic mild stress in rats. BMC Complement Altern. Med., 17.","DOI":"10.1186\/s12906-017-2012-9"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6334","DOI":"10.1017\/S0033291722003671","article-title":"The association between persistent cognitive difficulties and depression and functional outcomes in people with major depressive disorder","volume":"53","author":"Matcham","year":"2023","journal-title":"Psychol. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1080\/14740338.2022.2019705","article-title":"Vortioxetine in major depressive disorder: From mechanisms of action to clinical studies. An Updated Review","volume":"21","author":"Crespo","year":"2022","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1038\/s41386-018-0081-1","article-title":"Aberrant working memory processing in major depression: Evidence from multivoxel pattern classification","volume":"43","author":"Ghisu","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.brainres.2007.07.095","article-title":"Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model","volume":"1208","author":"Saitoh","year":"2008","journal-title":"Brain Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.bbr.2016.11.008","article-title":"Effects of repeated treatment with a delta opioid receptor agonist KNT-127 on hyperemotionality in olfactory-bulbectomized rats","volume":"323","author":"Gotoh","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"109511","DOI":"10.1016\/j.neuropharm.2023.109511","article-title":"KNT-127, a selective delta opioid receptor agonist, shows beneficial effects in the hippocampal dentate gyrus of a chronic vicarious social defeat stress mouse model","volume":"232","author":"Yoshioka","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"6489","DOI":"10.1167\/iovs.16-20673","article-title":"PI3K\/Akt Pathway: A role in \u03b4-opioid receptor-mediated RGC neuroprotection","volume":"58","author":"Husain","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Tanguturi, P., Pathak, V., Zhang, S., Moukha-Chafiq, O., Augelli-Szafran, C.E., and Streicher, J.M. (2021). Discovery of novel delta opioid receptor (DOR) inverse agonist and irreversible (non-competitive) antagonists. Molecules, 26.","DOI":"10.3390\/molecules26216693"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1007\/s43440-023-00526-9","article-title":"Therapeutic implications of phosphorylation- and dephosphorylation-dependent factors of cAMP-response element-binding protein (CREB) in neurodegeneration","volume":"75","author":"Khakha","year":"2023","journal-title":"Pharmacol. Rep."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.coph.2006.08.014","article-title":"Role of phosphodiesterases in neurological and psychiatric disease","volume":"7","author":"Hebb","year":"2007","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.ejphar.2016.06.034","article-title":"challenges for the pharmacological treatment of neurological and psychiatric disorders: Implications of the Ca(2+)\/cAMP intracellular signaling interaction","volume":"788","author":"Bergantin","year":"2016","journal-title":"Eur. J. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"808232","DOI":"10.3389\/fnbeh.2022.808232","article-title":"Selective \u03b4-opioid receptor agonist, KNT-127, facilitates contextual fear extinction via infralimbic cortex and amygdala in mice","volume":"16","author":"Kawaminami","year":"2022","journal-title":"Front. Behav. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"101967","DOI":"10.1016\/j.jchemneu.2021.101967","article-title":"Biphalin, a dimeric opioid peptide, reduces neonatal hypoxia-ischemia brain injury in mice by the activation of PI3K\/Akt signaling pathway","volume":"115","author":"Zhang","year":"2021","journal-title":"J. Chem. Neuroanat."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"778","DOI":"10.14336\/AD.2022.0912","article-title":"\u03b4-Opioid receptor, microglia and neuroinflammation","volume":"14","author":"Xu","year":"2023","journal-title":"Aging Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1016\/j.neubiorev.2004.09.002","article-title":"An overview of the tasks used to test working memory in rodents","volume":"28","author":"Dudchenko","year":"2004","journal-title":"Neurosci. Biobehav. Rev."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/2\/608\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:46:37Z","timestamp":1760103997000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/13\/2\/608"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,21]]},"references-count":74,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["jcm13020608"],"URL":"https:\/\/doi.org\/10.3390\/jcm13020608","relation":{},"ISSN":["2077-0383"],"issn-type":[{"type":"electronic","value":"2077-0383"}],"subject":[],"published":{"date-parts":[[2024,1,21]]}}}