{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T17:24:21Z","timestamp":1789925061889,"version":"4.0.1"},"reference-count":48,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T00:00:00Z","timestamp":1604361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In many social anxiety disorder (SAD) patients, the efficacy of antidepressant therapy is unsatisfactory. Here, we investigated whether mice deficient for the lysosomal glycoprotein acid sphingomyelinase (ASM\u2212\/\u2212) represent an appropriate tool to study antidepressant-resistant social fear. We also investigated whether neuropeptide Y (NPY) reduces this antidepressant-resistant social fear in ASM\u2212\/\u2212 mice, given that NPY reduced social fear in a mouse model of SAD, namely social fear conditioning (SFC). We show that neither chronic paroxetine nor chronic amitriptyline administration via drinking water were successful in reducing SFC-induced social fear in ASM\u2212\/\u2212 mice, while the same treatment reduced social fear in ASM+\/\u2212 mice and completely reversed social fear in ASM+\/+ mice. This indicates that the antidepressants paroxetine and amitriptyline reduce social fear via the ASM-ceramide system and that ASM\u2212\/\u2212 mice represent an appropriate tool to study antidepressant-resistant social fear. The intracerebroventricular administration of NPY, on the other hand, reduced social fear in ASM\u2212\/\u2212 mice, suggesting that NPY might represent an alternative pharmacotherapy for antidepressant-resistant social fear. These results suggest that medication strategies aimed at increasing brain NPY concentrations might improve symptoms of social fear in SAD patients who fail to respond to antidepressant treatments.<\/jats:p>","DOI":"10.3390\/ijms21218220","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T09:09:32Z","timestamp":1604394572000},"page":"8220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8096-3987","authenticated-orcid":false,"given":"Johannes","family":"Kornhuber","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7187-3181","authenticated-orcid":false,"given":"Iulia","family":"Zoicas","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/mpr.1359","article-title":"Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States","volume":"21","author":"Kessler","year":"2012","journal-title":"Int. J. Methods Psychiatr. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1586\/14737175.2014.934677","article-title":"Enhancing exposure therapy for anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder","volume":"14","author":"McGuire","year":"2014","journal-title":"Expert Rev. Neurother."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Williams, T., Hattingh, C.J., Kariuki, C.M., Tromp, S.A., van Balkom, A.J., Ipser, J.C., and Stein, D.J. (2017). Pharmacotherapy for social anxiety disorder (SAnD). Cochrane Database Syst. Rev., 10.","DOI":"10.1002\/14651858.CD001206.pub3"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0006-3223(01)01294-X","article-title":"Pharmacotherapy of social anxiety disorder","volume":"51","author":"Blanco","year":"2002","journal-title":"Biol. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cpr.2018.03.002","article-title":"Remission in CBT for adult anxiety disorders: A meta-analysis","volume":"61","author":"Springer","year":"2018","journal-title":"Clin. Psychol. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/0306-4522(86)90057-6","article-title":"Distribution of neuropeptide Y-like immunoreactivity in the rat central nervous system-II. Immunohistochemical analysis","volume":"18","author":"Emson","year":"1986","journal-title":"Neuroscience"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2607","DOI":"10.1523\/JNEUROSCI.09-08-02607.1989","article-title":"Neuropeptide Y receptor binding sites in rat brain: Differential autoradiographic localizations with 125I-peptide YY and 125I-neuropeptide Y imply receptor heterogeneity","volume":"9","author":"Lynch","year":"1989","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S0166-2236(96)01057-0","article-title":"Y-receptor subtypes-how many more?","volume":"20","author":"Blomqvist","year":"1997","journal-title":"Trends Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0166-2236(94)90046-9","article-title":"Effects of neuropeptide Y on the electrical properties of neurons","volume":"17","author":"Colmers","year":"1994","journal-title":"Trends Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1152\/ajpregu.2001.281.2.R417","article-title":"Increased blood pressure responses in neuropeptide Y transgenic rats","volume":"281","author":"Michalkiewicz","year":"2001","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"45","DOI":"10.2174\/1389203033380296","article-title":"Hormonal control of the neuropeptide Y system","volume":"4","author":"Magni","year":"2003","journal-title":"Curr. Protein Pept. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1016\/j.nut.2008.06.010","article-title":"NPY and its involvement in axon guidance, neurogenesis, and feeding","volume":"24","author":"Stanic","year":"2008","journal-title":"Nutrition"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1016\/0024-3205(84)90032-8","article-title":"Neuropeptide Y: Stimulation of feeding and drinking by injection into the paraventricular nucleus","volume":"35","author":"Stanley","year":"1984","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/S0306-4522(01)00116-6","article-title":"Neuropeptide Y Y1 receptor-mediated anxiolysis in the dorsocaudal lateral septum: Functional antagonism of corticotropin-releasing hormone-induced anxiety","volume":"104","author":"Kask","year":"2001","journal-title":"Neuroscience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0014-2999(99)00018-7","article-title":"Amygdalar neuropeptide Y Y1 receptors mediate the anxiolytic-like actions of neuropeptide Y in the social interaction test","volume":"368","author":"Sajdyk","year":"1999","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/S0893-133X(01)00403-1","article-title":"The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test","volume":"26","author":"Redrobe","year":"2002","journal-title":"Neuropsychopharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ynstr.2014.09.007","article-title":"Targeting the neuropeptide Y system in stress-related psychiatric disorders","volume":"1","author":"Enman","year":"2015","journal-title":"Neurobiol. Stress"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1097\/00008877-199504000-00001","article-title":"Behavioral effects of neuropeptide Y receptor agonists in the elevated plus-maze and fear-potentiated startle procedures","volume":"6","author":"Broqua","year":"1995","journal-title":"Behav. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.pbb.2004.12.009","article-title":"Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL\/6Jmice","volume":"80","author":"Karlsson","year":"2005","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.nlm.2013.04.005","article-title":"Role of NPY Y1 receptor on acquisition, consolidation and extinction on contextual fear conditioning: Dissociation between anxiety, locomotion and non-emotional memory behavior","volume":"103","author":"Lach","year":"2013","journal-title":"Neurobiol. Learn. Mem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12682","DOI":"10.1523\/JNEUROSCI.2305-08.2008","article-title":"The role of neuropeptide Y in the expression and extinction of fear-potentiated startle","volume":"28","author":"Gutman","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1177\/0269881119862529","article-title":"Neuropeptide Y reduces expression of social fear via simultaneous activation of Y1 and Y2 receptors","volume":"33","author":"Kornhuber","year":"2019","journal-title":"J. Psychopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1038\/npp.2011.329","article-title":"Social fear conditioning: A novel and specific animal model to study social anxiety disorder","volume":"37","author":"Toth","year":"2012","journal-title":"Neuropsychopharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Toth, I., Neumann, I.D., and Slattery, D.A. (2013). Social fear conditioning as an animal model of social anxiety disorder. Curr. Protoc. Neurosci.","DOI":"10.1002\/0471142301.ns0942s63"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1038\/nm.3214","article-title":"Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs","volume":"19","author":"Gulbins","year":"2013","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/S0014-5793(02)03482-8","article-title":"Sphingomyelinases: Enzymology and membrane activity","volume":"531","author":"Goni","year":"2002","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1515\/bchm3.1994.375.7.447","article-title":"The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts","volume":"375","author":"Hurwitz","year":"1994","journal-title":"Biol. Chem. Hoppe Seyler."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1159\/000315101","article-title":"Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): A novel pharmacological group of drugs with broad clinical applications","volume":"26","author":"Kornhuber","year":"2010","journal-title":"Cell Physiol. Biochem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/j.pnpbp.2010.03.005","article-title":"Behavioral and neurobiological consequences of prolonged glucocorticoid exposure in rats: Relevance to depression","volume":"34","author":"Sterner","year":"2010","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1159\/000126972","article-title":"Acute intracerebroventricular administration of neuropeptide Y stimulates corticosterone output and feeding but not insulin output in normal rats","volume":"63","author":"Sainsbury","year":"1996","journal-title":"Neuroendocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/sj.npp.1300899","article-title":"Systemic and intra-amygdala administration of glucocorticoid agonist and antagonist modulate extinction of conditioned fear","volume":"31","author":"Yang","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0196-9781(97)00266-0","article-title":"Cardiovascular actions of neuropeptide Y and social stress","volume":"19","author":"Klemfuss","year":"1998","journal-title":"Peptides"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.regpep.2004.03.011","article-title":"Central NPY receptor-mediated alteration of heart rate dynamics in mice during expression of fear conditioned to an auditory cue","volume":"120","author":"Tovote","year":"2004","journal-title":"Regul. Pept."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1038\/npp.2014.156","article-title":"Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum","volume":"39","author":"Zoicas","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bbr.2015.10.034","article-title":"Maternal separation facilitates extinction of social fear in adult male mice","volume":"297","author":"Zoicas","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.neuropharm.2016.03.054","article-title":"Neuropeptide S reduces fear and avoidance of con-specifics induced by social fear conditioning and social defeat, respectively","volume":"108","author":"Zoicas","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.bbr.2017.04.010","article-title":"Pharmacological modulation of metabotropic glutamate receptor subtype 5 and 7 impairs extinction of social fear in a time-point-dependent manner","volume":"328","author":"Slattery","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.cub.2018.02.044","article-title":"Oxytocin signaling in the lateral septum prevents social fear during lactation","volume":"28","author":"Menon","year":"2018","journal-title":"Curr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1007\/s00213-019-05199-y","article-title":"Effects of conditioned social fear on ethanol drinking and vice-versa in male mice","volume":"236","author":"Kornhuber","year":"2019","journal-title":"Psychopharmacology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.bbr.2009.10.028","article-title":"Anxiety responses in Balb\/c, c57 and CD-1 mice exposed to a novel open space test","volume":"207","author":"Michalikova","year":"2010","journal-title":"Behav. Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.bbr.2011.05.011","article-title":"Central effects of a local inflammation in three commonly used mouse strains with a different anxious phenotype","volume":"224","author":"Benatti","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Painsipp, E., K\u00f6fer, M.J., Sinner, F., and Holzer, P. (2011). Prolonged depression-like behavior caused by immune challenge: Influence of mouse strain and social environment. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020719"},{"key":"ref_43","first-page":"335","article-title":"Exploring female mice interstrain differences relevant for models of depression","volume":"9","author":"Roque","year":"2015","journal-title":"Front. Behav. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.bbr.2016.11.003","article-title":"Social behaviors and acoustic vocalizations in different strains of mice","volume":"320","author":"Faure","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.neulet.2016.11.035","article-title":"Outbred CD1 mice are as suitable as inbred C57BL\/6J mice in performing social tasks","volume":"637","author":"Hsieh","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"731","DOI":"10.3389\/fneur.2019.00731","article-title":"Enhanced alcohol preference and anxiolytic alcohol effects in Niemann-Pick disease model in mice","volume":"10","author":"Kalinichenko","year":"2019","journal-title":"Front. Neurol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Zoicas, I., Reichel, M., Gulbins, E., and Kornhuber, J. (2016). Role of acid sphingomyelinase in the regulation of social behavior and memory. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0162498"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6821","DOI":"10.1038\/s41598-017-07273-x","article-title":"Neuropeptide Y prolongs non-social memory and differentially affects acquisition, consolidation, and retrieval of non-social and social memory in male mice","volume":"7","author":"Kornhuber","year":"2017","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8220\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:28:30Z","timestamp":1760178510000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8220"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,3]]},"references-count":48,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21218220"],"URL":"https:\/\/doi.org\/10.3390\/ijms21218220","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,3]]}}}