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In the present study, we examined whether social experience since early life is one of the etiologies, with the involvement of the 5-HT1A receptors, and explored the potentially therapeutic action of the subchronic administration of buspirone, a partial 5-HT1A agonist. Rats were isolation reared (IR) since their weaning, and the depressive profile indexed by the forced-swim test (FST) was examined in adulthood. Nonspecific locomotor activity was used for the IR validation. Buspirone administration (1 mg\/kg\/day) was introduced for 14 days (week 9\u201311). The immobility score of the FST was examined before and after the buspirone administration. Tissue levels of serotonin (5-HT) and its metabolite 5-HIAA were measured in the hippocampus, the amygdala, and the prefrontal cortex. Efflux levels of 5-HT, dopamine (DA), and norepinephrine (NE) were detected in the hippocampus by brain dialysis. Finally, the full 5-HT1A agonist 8-OH-DPAT (0.5 mg\/kg) was acutely administered in both behavioral testing and the dialysis experiment. Our results showed (i) increased immobility time in the FST for the IR rats as compared to the social controls, which could not be reversed by the buspirone administration; (ii) IR-induced FST immobility in rats receiving buspirone was corrected by the 8-OH-DPAT; and (iii) IR-induced reduction in hippocampal 5-HT levels can be reversed by the buspirone administration. Our data indicated the 5-HT1A receptor-linked early life social experience as one of the mechanisms of later life depressive mood.<\/jats:p>","DOI":"10.3390\/ph17060717","type":"journal-article","created":{"date-parts":[[2024,6,3]],"date-time":"2024-06-03T10:08:38Z","timestamp":1717409318000},"page":"717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effects of Subchronic Buspirone Treatment on Depressive Profile in Socially Isolated Rats: Implication of Early Life Experience on 5-HT1A Receptor-Related Depression"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5881-7089","authenticated-orcid":false,"given":"Nian-Sheng","family":"Tzeng","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Tri-Service General Hospital, Taipei 114, Taiwan"},{"name":"Student Counseling Center, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-Yi","family":"Chung","sequence":"additional","affiliation":[{"name":"Laboratory of Cognitive Neuroscience, Department of Physiology and Biophysics, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Cheng","family":"Lin","sequence":"additional","affiliation":[{"name":"Laboratory of Cognitive Neuroscience, Department of Physiology and Biophysics, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pao-Yun","family":"Cheng","sequence":"additional","affiliation":[{"name":"Laboratory of Cognitive Neuroscience, Department of Physiology and Biophysics, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yia-Ping","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Cognitive Neuroscience, Department of Physiology and Biophysics, National Defense Medical Center, Taipei 114, Taiwan"},{"name":"Department of Psychiatry, Cheng Hsin General Hospital, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1002\/(SICI)1520-6394(1997)5:4<154::AID-DA2>3.0.CO;2-D","article-title":"Treatment-refractory depression: Definitions and characteristics","volume":"5","author":"Berman","year":"1997","journal-title":"Depress. Anxiety"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Pilon, D., Joshi, K., Sheehan, J.J., Zichlin, M.L., Zuckerman, P., Lefebvre, P., and Greenberg, P.E. (2019). Burden of treatment-resistant depression in Medicare: A retrospective claims database analysis. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0223255"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.psyneuen.2017.01.021","article-title":"An adverse early life environment can enhance stress resilience in adulthood","volume":"78","author":"Santarelli","year":"2017","journal-title":"Psychoneuroendocrinology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.neuroscience.2012.08.063","article-title":"From the stressed adolescent to the anxious and depressed adult: Investigations in rodent models","volume":"249","author":"McCormick","year":"2013","journal-title":"Neuroscience"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1097\/FBP.0000000000000679","article-title":"Buspirone, a 5-HT1A agonist attenuates social isolation-induced behavior deficits in rats: A comparative study with fluoxetine","volume":"33","author":"Aswar","year":"2022","journal-title":"Behav. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.neubiorev.2017.01.018","article-title":"Impact of adolescent social experiences on behavior and neural circuits implicated in mental illnesses","volume":"76","author":"Burke","year":"2017","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1016\/j.pnpbp.2011.03.002","article-title":"Critical period exists in the effects of isolation rearing on sensorimotor gating function but not locomotor activity in rat","volume":"35","author":"Liu","year":"2011","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Dimonte, S., Sikora, V., Bove, M., Morgese, M.G., Tucci, P., Schiavone, S., and Trabace, L. (2023). Social isolation from early life induces anxiety-like behaviors in adult rats: Relation to neuroendocrine and neurochemical dysfunctions. Biomed. Pharmacother., 158.","DOI":"10.1016\/j.biopha.2022.114181"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1177\/0956797611404085","article-title":"Serotonin transporter polymorphism interacts with childhood adversity to predict aspects of impulsivity","volume":"22","author":"Carver","year":"2011","journal-title":"Psychol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/B978-0-444-64125-0.00031-1","article-title":"Chapter 31\u2014The role of central serotonin in impulsivity, compulsivity, and decision-making: Comparative studies in experimental animals and humans","volume":"Volume 31","author":"Cunningham","year":"2020","journal-title":"Handbook of Behavioral Neuroscience"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0006-8993(95)00037-Q","article-title":"Effects of combined or separate 5,7-dihydroxytryptamine lesions of the dorsal and median raphe nuclei on responding maintained by a DRL 20s schedule of food reinforcement","volume":"675","author":"Fletcher","year":"1995","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1254\/jphs.14R05CP","article-title":"Potential role of serotonin1A receptors in post-weaning social isolation-induced abnormal behaviors in rodents","volume":"125","author":"Ago","year":"2014","journal-title":"J. Pharmacol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/0165-3806(90)90092-D","article-title":"5-HT1A receptors control neurite branching during development","volume":"56","author":"Sikich","year":"1990","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"80","DOI":"10.31083\/j.jin2204080","article-title":"Time-Dependent Effects of Buspirone versus Desipramine on the 5-Choice Serial Reaction Time Task in Rats Reared in Social Isolation: Implication of Early Life Experience and Motoric Impulsivity","volume":"22","author":"Tung","year":"2023","journal-title":"J. Integr. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.30773\/pi.2018.08.21.2","article-title":"Effects of 5HT1A Activation on Depression Profile Following 5-HT Depletion in Rats Lacking Social Attachment Since Weanling","volume":"15","author":"Chang","year":"2018","journal-title":"Psychiatry Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"193","DOI":"10.30773\/pi.2017.05.14.2","article-title":"Effects of 5HT1A Activation on Gating Profile Following 5HT Depletion in Rats Lacking Social Attachment Since Weanling","volume":"15","author":"Tai","year":"2018","journal-title":"Psychiatry Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1002\/syn.890010103","article-title":"Electrophysiological responses of serotoninergic dorsal raphe neurons to 5-HT1A and 5-HT1B agonists","volume":"1","author":"Sprouse","year":"1987","journal-title":"Synapse"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s40263-013-0071-0","article-title":"Serotonin 5-HT1A receptors as targets for agents to treat psychiatric disorders: Rationale and current status of research","volume":"27","author":"Celada","year":"2013","journal-title":"CNS Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0014-2999(82)90265-5","article-title":"Buspirone: Effects on central monoaminergic transmission--possible relevance to animal experimental and clinical findings","volume":"83","author":"Hjorth","year":"1982","journal-title":"Eur. J. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/0091-3057(89)90314-6","article-title":"Isolation-induced social behavioral deficit test: Effect of tranquilizing drugs","volume":"34","author":"Frances","year":"1989","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1037\/0022-006X.68.5.748","article-title":"Meta-analysis of risk factors for posttraumatic stress disorder in trauma-exposed adults","volume":"68","author":"Brewin","year":"2000","journal-title":"J. Consult. Clin. Psychol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1017\/S0033291706009019","article-title":"Early childhood factors associated with the development of post-traumatic stress disorder: Results from a longitudinal birth cohort","volume":"37","author":"Koenen","year":"2007","journal-title":"Psychol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110032","DOI":"10.1016\/j.mehy.2020.110032","article-title":"Early life social experience and adulthood impulsivity-Implications of central serotonergic system during development","volume":"143","author":"Chen","year":"2020","journal-title":"Med. Hypotheses"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1097\/00008877-199306000-00005","article-title":"Social isolation attenuates rat forebrain 5-HT release induced by KCI stimulation and exposure to a novel environment","volume":"4","author":"Bickerdike","year":"1993","journal-title":"Behav. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/BF02244319","article-title":"Effect of isolation rearing on 5-HT agonist-induced responses in the rat","volume":"105","author":"Wright","year":"1991","journal-title":"Psychopharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1016\/S0196-9781(00)00327-2","article-title":"Isolation-rearing of rats produces deficits as adults in the serotonergic innervation of hippocampus","volume":"21","author":"Zhou","year":"2000","journal-title":"Peptides"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.neubiorev.2013.11.009","article-title":"Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects","volume":"38","author":"Mahar","year":"2014","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/0028-3908(95)00102-C","article-title":"The effect of 5-HT1A receptor ligands in a chronic mild stress model of depression","volume":"34","author":"Moryl","year":"1995","journal-title":"Neuropharmacology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1001\/jamapsychiatry.2017.0025","article-title":"Reevaluating the Efficacy and Predictability of Antidepressant Treatments: A Symptom Clustering Approach","volume":"74","author":"Chekroud","year":"2017","journal-title":"JAMA Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"448","DOI":"10.4088\/JCP.v62n0608","article-title":"Patients with severe depression may benefit from buspirone augmentation of selective serotonin reuptake inhibitors: Results from a placebo-controlled, randomized, double-blind, placebo wash-in study","volume":"62","author":"Appelberg","year":"2001","journal-title":"J. Clin. Psychiatry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0006-3223(02)01643-8","article-title":"Is there a role for 5-HT1A agonists in the treatment of depression?","volume":"53","author":"Blier","year":"2003","journal-title":"Biol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0893-133X(96)00242-4","article-title":"Selective activation of postsynaptic 5-HT1A receptors induces rapid antidepressant response","volume":"16","author":"Blier","year":"1997","journal-title":"Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/0028-3908(88)90079-2","article-title":"Responses of hippocampal pyramidal cells to putative serotonin 5-HT1A and 5-HT1B agonists: A comparative study with dorsal raphe neurons","volume":"27","author":"Sprouse","year":"1988","journal-title":"Neuropharmacology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.psyneuen.2017.10.007","article-title":"Sex differences in behavioral and neurochemical effects of gonadectomy and aromatase inhibition in rats","volume":"87","author":"Kokras","year":"2018","journal-title":"Psychoneuroendocrinology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1093\/sleep\/17.7.583","article-title":"Sleep deprivation in the rat: XVIII. Regional brain levels of monoamines and their metabolites","volume":"17","author":"Bergmann","year":"1994","journal-title":"Sleep"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1007\/s11064-006-9096-9","article-title":"Regional variations of 5HT concentrations in Rorasg (staggerer) mutants","volume":"31","author":"Lalonde","year":"2006","journal-title":"Neurochem. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1016\/S0006-3223(99)00322-4","article-title":"5-HT(1A) agonist potential of pindolol: Electrophysiologic studies in the dorsal raphe nucleus and hippocampus","volume":"47","author":"Sprouse","year":"2000","journal-title":"Biol. Psychiatry"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.neuroscience.2004.05.031","article-title":"Estrogen treatment increases the levels of regulator of G protein signaling-Z1 in the hypothalamic paraventricular nucleus: Possible role in desensitization of 5-hydroxytryptamine1A receptors","volume":"127","author":"Carrasco","year":"2004","journal-title":"Neuroscience"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1592\/phco.27.9.1339","article-title":"Agitation associated with aripiprazole initiation","volume":"27","author":"Lea","year":"2007","journal-title":"Pharmacotherapy"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.brainres.2010.05.054","article-title":"Chronic buspirone treatment decreases 5-HT1B receptor densities and the serotonin transporter but increases the density of 5-HT2A receptors in the bulbectomized rat model of depression: An autoradiographic study","volume":"23","author":"Sato","year":"2010","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"9283","DOI":"10.1016\/j.bmc.2008.09.005","article-title":"The molecular interactions of buspirone analogues with the serotonin transporter","volume":"16","author":"Chilmonczyk","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.bbi.2015.08.003","article-title":"Disruptions of sensorimotor gating, cytokines, glycemia, monoamines, and genes in both sexes of rats reared in social isolation can be ameliorated by oral chronic quetiapine administration","volume":"51","author":"Ko","year":"2016","journal-title":"Brain Behav. Immun."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lin, C.C., Chen, T.Y., Cheng, P.Y., and Liu, Y.P. (2020). Early life social experience affects adulthood fear extinction deficit and associated dopamine profile abnormalities in a rat model of PTSD. Prog. Neuro-Psychopharmacol. Biol. Psychiatry, 101.","DOI":"10.1016\/j.pnpbp.2020.109914"},{"key":"ref_44","unstructured":"Paxinos, G., and Watson, C. (2008). The Rat Brain in Stereotaxic Coordinates: Hard Cover Edition, Elsevier."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/6\/717\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:52:11Z","timestamp":1760107931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/6\/717"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,1]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,6]]}},"alternative-id":["ph17060717"],"URL":"https:\/\/doi.org\/10.3390\/ph17060717","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,1]]}}}