{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T00:56:12Z","timestamp":1768697772114,"version":"3.49.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Sigma-1 receptor (\u03c3<jats:sub>1<\/jats:sub>R) downregulation in male mice is known to cause a depressive-like phenotype. The nucleus accumbens (NAc), a region associated with affective regulation, has high levels of \u03c3<jats:sub>1<\/jats:sub>R. Here, we investigated the effect of repeated inhibition of \u03c3<jats:sub>1<\/jats:sub>R in the NAc on depressive-like behaviors and synaptic plasticity by microinjecting \u03c3<jats:sub>1<\/jats:sub>R antagonist NE-100 into NAc nuclei in mice (NE-100 mice); this was followed by behavioral tests and field potentials recordings. We first examined the effect of NE-100 administration on \u03c3<jats:sub>1<\/jats:sub>R expression and found that cell surface levels of \u03c3<jats:sub>1<\/jats:sub>R were significantly reduced in the NAc of NE-100 mice. Compared to control mice, NE-100 mice exhibited significantly prolonged immobility in forced swim test (FST) and tail suspension test (TST), impaired long-term depression (LTD) as well as multi-spike waveform field excitatory postsynaptic potential (fEPSP) with an extended duration and an increased paired-pulse ratio (PPR). Reduced levels of GABA<jats:sub>A<\/jats:sub> receptor (GABA<jats:sub>A<\/jats:sub>R)-\u03b11, -\u03b12, -\u03b22, and -\u03b23 subunits, membrane D2R, and PKC phosphorylation in the NAc were observed in NE-100 mice. Activation of GABA<jats:sub>A<\/jats:sub>R by muscimol corrected the extended fEPSP duration and increased PPR, restored LTD maintenance as well as alleviated depressive-like behaviors in NE-100 mice. The decline of PKC phosphorylation in the NAc of NE-100 mice was corrected by injecting NAc with quinpirole, a D2R agonist. Injections of quinpirole or PMA (a PKC activator) into NAc of NE-100 mice rescued the expression levels of GABA<jats:sub>A<\/jats:sub>R, and alleviated the increase in PPR and impairment in LTD; these effects were sensitive to GF109203X, a PKC inhibitor. Furthermore, injecting NAc with quinpirole or PMA relieved depressive-like behaviors in NE-100 mice. Collectively, these results indicate that repeated inhibition of \u03c3<jats:sub>1<\/jats:sub>R in the NAc reduces D2R-mediated PKC phosphorylation and suppresses GABA<jats:sub>A<\/jats:sub>R expression, thus impairing LTD maintenance and leading to depressive-like behaviors.<\/jats:p>","DOI":"10.3389\/fnmol.2022.959224","type":"journal-article","created":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T14:08:22Z","timestamp":1664546902000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Repeated inhibition of sigma-1 receptor suppresses GABAA receptor expression and long-term depression in the nucleus accumbens leading to depressive-like behaviors"],"prefix":"10.3389","volume":"15","author":[{"given":"Yaoyao","family":"Qin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weixing","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunpeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sha","family":"Sha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8143","DOI":"10.1073\/pnas.1917423117","article-title":"Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3\u03b2-dependent modulation of Kv4.2 channels","volume":"117","author":"Aceto","year":"2020","journal-title":"Proc. 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