{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:57:42Z","timestamp":1785862662114,"version":"3.56.0"},"reference-count":53,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"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>Neuropeptide Y (NPY) has anxiolytic-like effects and facilitates the extinction of cued and contextual fear in rodents. We previously showed that intracerebroventricular administration of NPY reduces the expression of social fear in a mouse model of social fear conditioning (SFC) and localized these effects to the dorsolateral septum (DLS) and central amygdala (CeA). In the present study, we aimed to identify the receptor subtypes that mediate these local effects of NPY. We show that NPY (0.1 nmol\/0.2 \u00b5L\/side) reduced the expression of SFC-induced social fear in a brain region- and receptor-specific manner in male mice. In the DLS, NPY reduced the expression of social fear by acting on Y2 receptors but not on Y1 receptors. As such, prior administration of the Y2 receptor antagonist BIIE0246 (0.2 nmol\/0.2 \u03bcL\/side) but not the Y1 receptor antagonist BIBO3304 trifluoroacetate (0.2 nmol\/0.2 \u03bcL\/side) blocked the effects of NPY in the DLS. In the CeA, however, BIBO3304 trifluoroacetate but not BIIE0246 blocked the effects of NPY, suggesting that NPY reduced the expression of social fear by acting on Y1 receptors but not Y2 receptors within the CeA. This study suggests that at least two distinct receptor subtypes are differentially recruited in the DLS and CeA to mediate the effects of NPY on the expression of social fear.<\/jats:p>","DOI":"10.3390\/ijms221810142","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"10142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Neuropeptide Y Reduces Social Fear in Male Mice: Involvement of Y1 and Y2 Receptors in the Dorsolateral Septum and Central Amygdala"],"prefix":"10.3390","volume":"22","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":[[2021,9,20]]},"reference":[{"key":"ref_1","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_2","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_3","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0166-2236(98)01284-3","article-title":"Neuropeptide Y: Emerging evidence for a functional role in seizure modulation","volume":"22","author":"Vezzani","year":"1999","journal-title":"Trends Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R417","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. Integr. Comp. Physiol."},{"key":"ref_5","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_6","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_7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1523\/JNEUROSCI.13-01-00073.1993","article-title":"Comparative characterization and autoradiographic distribution of neuropeptide Y receptor subtypes in the rat brain","volume":"13","author":"Dumont","year":"1993","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1002\/(SICI)1098-2396(199602)22:2<139::AID-SYN7>3.0.CO;2-E","article-title":"Autoradiographic distribution of [125I]Leu31,Pro34]PYY and [125I]PYY3-36 binding sites in the rat brain evaluated with two newly developed Y1 and Y2 receptor radioligands","volume":"22","author":"Dumont","year":"1996","journal-title":"Synapse"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1431","DOI":"10.1046\/j.1460-9568.1999.00553.x","article-title":"Regional distribution of Y-receptor subtype mRNAs in rat brain","volume":"11","author":"Parker","year":"1999","journal-title":"Eur. J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2111","DOI":"10.1016\/0024-3205(85)90583-1","article-title":"Neuropeptide Y (NPY) binding sites in rat brain labeled with 125I-Bolton-Hunter NPY: Comparative potencies of various polypeptides on brain NPY binding and biological responses in the rat vas deferens","volume":"37","author":"Chang","year":"1985","journal-title":"Life Sci."},{"key":"ref_11","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":"Quidt","year":"1986","journal-title":"Neuroscience"},{"key":"ref_12","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_13","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1007\/BF00441953","article-title":"Centrally administered neuropeptide Y (NPY) produces anxiolytic-like effects in animal anxiety models","volume":"98","author":"Heilig","year":"1989","journal-title":"Psychopharmacology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/npp.1993.35","article-title":"Anxiolytic-Like Action of Neuropeptide Y: Mediation by Y1 Receptors in Amygdala, and Dissociation from Food Intake Effects","volume":"8","author":"Heilig","year":"1993","journal-title":"Neuropsychopharmacology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Kornhuber, J., and Zoicas, I. (2021). Brain Region-Dependent Effects of Neuropeptide Y on Conditioned Social Fear and Anxiety-Like Behavior in Male Mice. Int. J. Mol. 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Behav."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1038\/sj.npp.1301258","article-title":"The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide, Y","volume":"32","author":"Domin","year":"2007","journal-title":"Neuropsychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1093\/brain\/awm033","article-title":"Viral vector-induced amygdala NPY overexpression reverses increased alcohol intake caused by repeated deprivations in Wistar rats","volume":"130","author":"Thorsell","year":"2007","journal-title":"Brain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.alcohol.2015.11.001","article-title":"Ethanol-induced anxiolysis and neuronal activation in the amygdala and bed nucleus of the stria terminalis","volume":"50","author":"Sharko","year":"2016","journal-title":"Alcohol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/jnr.20200","article-title":"Differential roles for neuropeptide Y Y1 and Y5 receptors in anxiety and sedation","volume":"77","author":"Lindberg","year":"2004","journal-title":"J. Neurosci. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/S0196-9781(97)00298-2","article-title":"Neuropeptide Y Produces Anxiety Via Y2-Type Receptors","volume":"19","author":"Nakajima","year":"1998","journal-title":"Peptides"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.1016\/j.peptides.2006.07.020","article-title":"Anxiolytic-like effect of the selective Neuropeptide Y Y2 receptor antagonist BIIE0246 in the elevated plus-maze","volume":"27","author":"Bacchi","year":"2006","journal-title":"Peptides"},{"key":"ref_24","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_25","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_26","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0091-3057(01)00679-7","article-title":"Neuropeptide Y-Y2 receptors mediate anxiety in the amygdala","volume":"71","author":"Sajdyk","year":"2002","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_27","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_28","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\/6J mice","volume":"80","author":"Karlsson","year":"2005","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_29","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_30","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_31","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s00213-009-1610-8","article-title":"Fear-reducing effects of intra-amygdala neuropeptide Y infusion in animal models of conditioned fear: An NPY Y1 receptor independent effect","volume":"206","author":"Fendt","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1016\/j.neuroscience.2009.09.079","article-title":"Effect of pharmacological manipulations of neuropeptide Y and corticotropin-releasing factor neurotransmission on incubation of conditioned fear","volume":"164","author":"Pickens","year":"2009","journal-title":"Neuroscience"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1111\/j.1476-5381.2012.01872.x","article-title":"NPY controls fear conditioning and fear extinction by combined action on Y\u2081 and Y\u2082 receptors","volume":"166","author":"Verma","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1016\/j.neuropharm.2015.08.038","article-title":"NPY Y2 receptors in the central amygdala reduce cued but not contextual fear","volume":"99","author":"Verma","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1111\/bph.13456","article-title":"Pancreatic polypeptide and its central Y 4 receptors are essential for cued fear extinction and permanent suppression of fear","volume":"173","author":"Verma","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_36","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_37","doi-asserted-by":"crossref","unstructured":"Kornhuber, J., and Zoicas, I. (2020). Neuropeptide Y as Alternative Pharmacotherapy for Antidepressant-Resistant Social Fear. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21218220"},{"key":"ref_38","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_39","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_40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.brainresrev.2004.04.009","article-title":"Regulation of affect by the lateral septum: Implications for neuropsychiatry","volume":"46","author":"Sheehan","year":"2004","journal-title":"Brain Res. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.npep.2015.09.007","article-title":"The role of Neuropeptide Y in fear conditioning and extinction","volume":"55","author":"Tasan","year":"2016","journal-title":"Neuropeptides"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1002\/(SICI)1096-9861(19981221)402:3<372::AID-CNE6>3.0.CO;2-2","article-title":"Species differences in the expression and distribution of the neuropeptide Y Y1, Y2, Y4, and Y5 receptors in rodents, guinea pig, and primates brains","volume":"402","author":"Dumont","year":"1998","journal-title":"J. Comp. Neurol."},{"key":"ref_43","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_44","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_45","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_46","doi-asserted-by":"crossref","first-page":"R868","DOI":"10.1016\/j.cub.2007.08.005","article-title":"The amygdala","volume":"17","author":"LeDoux","year":"2007","journal-title":"Curr. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/S0896-6273(00)80775-8","article-title":"Why We Think Plasticity Underlying Pavlovian Fear Conditioning Occurs in the Basolateral Amygdala","volume":"23","author":"Fanselow","year":"1999","journal-title":"Neuron"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Wang, J., Tian, Y., Zeng, L.-H., and Xu, H. (2020). Prefrontal Disinhibition in Social Fear: A Vital Action of Somatostatin Interneurons. Front. Cell. Neurosci., 14.","DOI":"10.3389\/fncel.2020.611732"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1038\/mp.2016.1","article-title":"Overshadowed by the amygdala: The bed nucleus of the stria terminalis emerges as key to psychiatric disorders","volume":"21","author":"Lebow","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Kornhuber, J., and Zoicas, I. (2020). Neuropeptide Y prolongs non-social memory in a brain region- and receptor-specific way in male mice. Neuropharmacology, 175.","DOI":"10.1016\/j.neuropharm.2020.108199"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Kornhuber, J., and Zoicas, I. (2020). Social fear memory requires two stages of protein synthesis in mice. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155537"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/0471142301.ns0942s63","article-title":"Social Fear Conditioning as an Animal Model of Social Anxiety Disorder","volume":"63","author":"Toth","year":"2013","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00441-013-1636-4","article-title":"Animal models of social avoidance and social fear","volume":"354","author":"Toth","year":"2013","journal-title":"Cell Tissue Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10142\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:34Z","timestamp":1760166154000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":53,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810142"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810142","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,20]]}}}