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Sigma-2 receptor
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<h2 id="classification">Classification</h2> <p>The sigma-2 receptor is located in the <a href="/facts/Lipid_raft/9Gyy5p4H">lipid raft</a>.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> The sigma-2 receptor is found in several areas of the brain, including high densities in the <a href="/facts/Cerebellum/kBRS2Lou">cerebellum</a>, <a href="/facts/Motor_cortex/oQ2w0g3S">motor cortex</a>, <a href="/facts/Hippocampus/X7CqbP8X">hippocampus</a>, and <a href="/facts/Substantia_nigra/qDpsqpcJ">substantia nigra</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> It is also highly expressed in the <a href="/facts/Lungs/gTWXI6Fj">lungs</a>, <a href="/facts/Liver/Rtp4Fk2b">liver</a>, and <a href="/facts/Kidney/HBspPrv9">kidneys</a>.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h2 id="function">Function</h2> <p>The sigma-2 receptor takes part in a number of normal-function roles such as cholesterol homeostasis.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a><a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a><a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h3>Non-neuronal signaling</h3> <p>Binding of a number of <a href="/facts/Hormone/WFnBnINJ">hormones</a> and <a href="/facts/Steroid/4AhMbgXt">steroids</a>, including <a href="/facts/Testosterone/uUumdhAz">testosterone</a>, <a href="/facts/Progesterone/WEj2TGRm">progesterone</a>, and <a href="/facts/Cholesterol/TnfPlYc1">cholesterol</a>, has been found to occur with sigma-2 receptors,<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> though in some cases with lower <a href="/facts/Affinity_(pharmacology)/44QLL4eU">affinity</a> than to the <a href="/facts/Sigma-1_receptor/qje6l9GW">sigma-1 receptor</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> Signaling caused by this binding is thought to occur via a calcium secondary messenger<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> and calcium-dependent phosphorylation,<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> and in association with <a href="/facts/Sphingolipids/qdG4l8DQ">sphingolipids</a><a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> following <a href="/facts/Endoplasmic_reticulum/DVbLA7GE">endoplasmic reticulum</a> release of <a href="/facts/Calcium/hf252CC0">calcium</a>.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> Known effects include decrease of expression of effectors in the <a href="/facts/MTOR/5l2dVa1p">mTOR</a> pathway, and suppression of <a href="/facts/Cyclin_D1/okobJlFK">cyclin D1</a> and <a href="/facts/PARP-1/ct3W2NDG">PARP-1</a>.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> </p> <h3>Neuronal signaling</h3> <p>Signaling action in <a href="/facts/Neuron/G7CyTVdH">neurons</a> by sigma-2 receptors and their associated <a href="/facts/Ligand/6etB3qeW">ligands</a> results in modulation of <a href="/facts/Action_potential/Sz8yCRqx">action potential</a> firing by regulation of <a href="/facts/Calcium_channel/4C7vusSt">calcium channels</a> and <a href="/facts/Potassium_channel/0QHmrHPn">potassium channels</a>.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> They also are involved in synaptic vesicular release and modulation of <a href="/facts/Dopamine/5gNy8Xkd">dopamine</a>, <a href="/facts/Serotonin/EzY58q4a">serotonin</a>, and <a href="/facts/Glutamate/7oXbNcvu">glutamate</a>,<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a> with activation and increase of the <a href="/facts/Dopaminergic/y2PcAHB2">dopaminergic</a>, <a href="/facts/Serotonin/EzY58q4a">serotonergic</a>, and <a href="/facts/Noradrenergic/AjTIC9ox">noradrenergic</a> activity of neurons.<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a><a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p> <h3>Cell proliferation</h3> <p>Sigma-2 receptors have been found to be highly expressed in proliferating cells, including <a href="/facts/Tumor_cell/K0ytzmPz">tumor cells</a>,<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> and to play a role in the differentiation, morphology, and survival of those cells.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> By interacting with EGFR membrane proteins sigma-2 receptors play a role in the regulation of signals further downstream such as PKC and RAF. Both <a href="/facts/Protein_kinase_C/6WSQgAWv">PKC</a> and <a href="/facts/Raf_kinase/tfypET06">Raf kinase</a> up regulate transcription and cell proliferation.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> </p> <h2 id="ligands">Ligands</h2> <p>Ligands of the sigma-2 receptor are <a href="/facts/Exogenous/yHXbIsAa">exogenous</a> and internalized by <a href="/facts/Endocytosis/NJjChLNj">endocytosis</a>, and can act as either <a href="/facts/Agonist/nz8U5NNp">agonists</a> or <a href="/facts/Antagonist/AssYgnt1">antagonists</a>. They can typically be classified into four groups, which are structurally related. It is not entirely understood how binding to the sigma-2 receptor occurs.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> Proposed models commonly include one small and one bulky <a href="/facts/Hydrophobic/Ifya0CXQ">hydrophobic</a> pocket, <a href="/facts/Electrostatic/bxkuW6s4">electrostatic</a> hydrogen interactions, and less commonly a third hydrophobic pocket. </p> <table><tbody><tr><th>Class Name<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></th><th>Common compounds<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a></th></tr><tr><td>6,7-Dimethoxytetrahydroisoquinoline analogs</td><td>RHM-4, [18F]ISO-1, [125I]ISO-2</td></tr><tr><td><a href="/facts/Tropane/ed8aqaw8">Tropane</a> and granatane analogs</td><td>BIMU-1, <a href="/facts/FEM-1689/evSCetkd">FEM-1689</a>, SW107, SW116, SW120</td></tr><tr><td><a href="/facts/Indole/HT72P6e6">Indole</a> analogs</td><td><a href="/facts/Siramesine/IaNn6kDt">Siramesine</a>, <a href="/facts/Ibogaine/EImBELph">Ibogaine</a></td></tr><tr><td>Cyclohexylpiperazine analogs</td><td><a href="/facts/PB-28/C6qdTvpL">PB28</a>, F281</td></tr></tbody></table> <p>A study of the four groups has revealed that a basic nitrogen and at least one hydrophobic moiety is needed to bind a sigma-2 receptor. In addition, there are molecular characteristics that increase the selectivity for sigma-2 receptors, which include bulky hydrophobic regions, nitrogen-carboxylic interaction, and additional basic nitrogens.<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a> </p><p>Since its discovery in 1990, the sigma-2 receptor has been considered an <a href="/facts/Orphan_receptor/30Xum2PA">orphan receptor</a>; however, in 2021 <a href="/facts/20S-Hydroxycholesterol/o2LUfH0x">20S-hydroxycholesterol</a> was identified as the putative <a href="/facts/Endogenous_ligand/44QLL4eU">endogenous ligand</a>.<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a><a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a> </p><p>Another ligand is <a href="/facts/Lu_29-252/1ao1rlt5">Lu 29-252</a>. </p> <h2 id="diagnostic-use">Diagnostic use</h2> <p>Sigma-2 receptors are highly expressed in breast, ovarian, lung cancers, brain, bladder, colon cancers, and <a href="/facts/Melanoma/qdT7E97Y">melanoma</a>.<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a><a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a> This novelty makes them a valuable <a href="/facts/Biomarker/nk2LgXtq">biomarker</a> for identifying cancerous tissues. Furthermore, studies have shown that they are more highly expressed in <a href="/facts/Malignant_tumor/PVW6n1D0">malignant tumors</a> than dormant tumors.<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a> </p><p><a href="/facts/Exogenous/yHXbIsAa">Exogenous</a> sigma-2 receptor <a href="/facts/Ligand/6etB3qeW">ligands</a> have been altered to be neuronal-tracers, used to map cells and their connections. These tracers have high <a href="/facts/Chemoselectivity/hy4R50B3">selectivity</a> and <a href="/facts/Affinity_(pharmacology)/44QLL4eU">affinity</a> for sigma-2 receptors, and high <a href="/facts/Lipophilicity/AWpsR8Xe">lipophilicity</a>, making them ideal for usage in the brain.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> Because sigma-2 receptors are highly expressed in tumor cells and are part of the cell proliferation mechanism, <a href="/facts/PET_scan/5SmcW6qz">PET scans</a> using sigma-2 targeted tracers can reveal if a tumor is proliferating and what its growth rate is.<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> </p> <h2 id="therapeutic-use">Therapeutic use</h2> <h3>Neurodegenerative and Neuro-ophthalmic Diseases</h3> <p>The sigma-2 receptor is expressed in <a href="/facts/Brain/Xo5ABfXl">brain</a><a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> and <a href="/facts/Retina/v0ISNX2S">retinal</a> cells<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a><a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a> where it regulates key pathways involved in age-related diseases such as <a href="/facts/Alzheimer%2527s_disease/w7Ad6tdg">Alzheimer's disease</a> and synucleinopathies such as <a href="/facts/Parkinson%2527s_disease/xpekKj6x">Parkinson's disease</a> and <a href="/facts/Dementia_with_Lewy_bodies/Sw6vTGkh">dementia with Lewy bodies</a>,<a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a> as well as dry age-related macular degeneration (<a href="/facts/Dry_AMD/9pFARaka">dry AMD</a>). The normal activity of processes regulated by sigma-2, such as protein trafficking and <a href="/facts/Autophagy/kJC4QM9l">autophagy</a>, is impaired by cellular stresses such as oxidative stress and the build-up of <a href="/facts/Amyloid-%25CE%25B2/QkXy91f9">amyloid-β</a> and <a href="/facts/%25CE%2591-synuclein/rMau6thf">α-synuclein</a> <a href="/facts/Oligomers/v7oDY8zu">oligomers</a>.<a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> Studies support that sigma-2 modulators can rescue biological processes that are impaired in neurodegenerative diseases.<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a><a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a> </p><p>In vitro studies of experimental sigma-2 receptor modulators demonstrated an ability to prevent the binding of <a href="/facts/Amyloid-%25CE%25B2/QkXy91f9">amyloid-β</a> oligomers to neurons and also to displace bound <a href="/facts/Amyloid-%25CE%25B2/QkXy91f9">amyloid-β</a> oligomers from neuronal receptors.<a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> In addition, transgenic mice treated sigma-2 receptor modulators performed significantly better in the Morris water maze task than did vehicle-treated mice.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> Taken together, these studies suggest that sigma-2 receptor modulation may be a viable approach for treating certain <a href="/facts/Neurodegenerative_diseases/HTDrVEqc">neurodegenerative diseases</a> of the <a href="/facts/Central_nervous_system/k8I6To97">CNS</a> and <a href="/facts/Retina/v0ISNX2S">retina</a>. </p> <h3>Neuropsychiatric</h3> <p>Due to the binding capabilities of <a href="/facts/Antipsychotic/7bNTg7T3">antipsychotic</a> drugs<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a><a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> and various <a href="/facts/Neurotransmitter/LlpYFSU3">neurotransmitters</a> associated with mood,<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> the sigma-2 receptor is a viable target for therapies related to <a href="/facts/Neuropsychiatric_disorder/EPNjFtFf">neuropsychiatric disorders</a> and modulation of emotional response.<a class="footnote-ref" id="fnref:50" href="#fn:50"><sup>50</sup></a> It is thought to be involved in the <a href="/facts/Pathophysiology/Tp3Dny0c">pathophysiology</a> of <a href="/facts/Schizophrenia/FMP4lQ57">schizophrenia</a>,<a class="footnote-ref" id="fnref:51" href="#fn:51"><sup>51</sup></a> and sigma-2 receptors have been shown to be less abundant in schizophrenic patients.<a class="footnote-ref" id="fnref:52" href="#fn:52"><sup>52</sup></a> Additionally, PCP, which is an NMDA antagonist, can induce <a href="/facts/Schizophrenia/FMP4lQ57">schizophrenia</a>,<a class="footnote-ref" id="fnref:53" href="#fn:53"><sup>53</sup></a> while sigma-2 receptor activation has been shown to antagonize effects of <a href="/facts/Phencyclidine/4LaNo5Cl">PCP</a>, implying <a href="/facts/Antipsychotic/7bNTg7T3">antipsychotic</a> capabilities.<a class="footnote-ref" id="fnref:54" href="#fn:54"><sup>54</sup></a> Sigma receptors are a potential target for treatment of <a href="/facts/Dystonia/j0jeA0XD">dystonia</a>, given high densities in affected regions of the brain.<a class="footnote-ref" id="fnref:55" href="#fn:55"><sup>55</sup></a> Anti-ischemics <a href="/facts/Ifenprodil/SqWzThA5">ifenprodil</a> and <a href="/facts/Eliprodil/LcJTSPe8">eliprodil</a>, the binding of which increases blood flow, have also shown affinity to sigma receptors.<a class="footnote-ref" id="fnref:56" href="#fn:56"><sup>56</sup></a> In experimental trials in mice and rats, the sigma-2 receptor ligand <a href="/facts/Siramesine/IaNn6kDt">siramesine</a> caused reduced anxiety and displayed antidepressant capabilities,<a class="footnote-ref" id="fnref:57" href="#fn:57"><sup>57</sup></a> while other studies have shown inhibition of selective sigma receptor <a href="/facts/Radioligand/BD7LXsdM">radioligands</a> by antidepressants, in the mouse and rat brain.<a class="footnote-ref" id="fnref:58" href="#fn:58"><sup>58</sup></a> </p> <h3>Cancer</h3> <p>Sigma-2 receptors have been associated with <a href="/facts/Pancreatic_cancer/6h9GIInW">pancreatic cancer</a>, <a href="/facts/Lung_cancer/LHLdR454">lung cancer</a>, <a href="/facts/Breast_cancer/6hME580v">breast cancer</a>, <a href="/facts/Melanoma/qdT7E97Y">melanoma</a>, <a href="/facts/Prostate_cancer/Mx7XuDhm">prostate cancer</a>, and <a href="/facts/Ovarian_cancer/fsWbh3Tn">ovarian cancer</a>. <a href="/facts/Tumor/K0ytzmPz">Tumor</a> cells are shown to over-express sigma-2 receptors, allowing for potential cancer therapies as many sigma-2 receptor mediated cell responses happen only in tumor cells.<a class="footnote-ref" id="fnref:59" href="#fn:59"><sup>59</sup></a> Tumor cell responses are modulated via <a href="/facts/Ligand_binding/44QLL4eU">ligand binding</a>. Sigma receptor ligands can act as <a href="/facts/Agonist/nz8U5NNp">agonists</a> or <a href="/facts/Antagonist/AssYgnt1">antagonists</a>, generating different cellular responses. <a href="/facts/Agonist/nz8U5NNp">Agonists</a> <a href="/facts/Enzyme_inhibitor/MkFwGXHJ">inhibit</a> tumor <a href="/facts/Cell_proliferation/Jp3hWo2t">cell proliferation</a> and induce <a href="/facts/Apoptosis/8dVzSm4y">apoptosis</a>, which is thought to be triggered by <a href="/facts/Caspase-3/FpjEwtwR">caspase-3</a> activity. Antagonists promote tumor cell proliferation, but this mechanism is less understood.<a class="footnote-ref" id="fnref:60" href="#fn:60"><sup>60</sup></a> Sigma receptor ligands have been conjugated to <a href="/facts/Nanoparticle/k8kNxX4E">nanoparticles</a> and peptides to deliver cancer treatment to tumor cells without targeting other tissues.<a class="footnote-ref" id="fnref:61" href="#fn:61"><sup>61</sup></a> The success with these methods have been limited to <a href="/facts/In_vitro/evp3hAX6">in vitro</a> trials. Additionally, using sigma-2 receptors to target tumor cells allows for synergizing anti-cancer drug therapies. Some studies have shown that certain sigma receptor inhibitors increase cancer cells' susceptibility to <a href="/facts/Chemotherapy/fWTLbaUT">chemotherapy</a>.<a class="footnote-ref" id="fnref:62" href="#fn:62"><sup>62</sup></a> Other types of binding to sigma-2 receptors increases <a href="/facts/Cytotoxicity/SQuTTLoL">cytotoxicity</a> of doxorubicin, antinomyocin, and other cancer cell killing drugs.<a class="footnote-ref" id="fnref:63" href="#fn:63"><sup>63</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Sigma-1_receptor/qje6l9GW">Sigma-1 receptor</a></li> <li><a href="/facts/Sigma_receptor/JpFeF344">Sigma receptor</a></li> <li><a href="/facts/SAS-1121/5SH3Cfwu">SAS-1121</a>, a tool compound preferentially binding to the sigma-2 receptor</li></ul> <h2 id="external-links">External links</h2> <ul><li><a href="https://meshb.nlm.nih.gov/record/ui?name=sigma-2+receptor">sigma-2+receptor</a> at the U.S. National Library of Medicine <a href="/facts/Medical_Subject_Headings/C57g2JuF">Medical Subject Headings</a> (MeSH)</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>van Waarde A, Rybczynska AA, Ramakrishnan NK, Ishiwata K, Elsinga PH, Dierckx RA (October 2015). "Potential applications for sigma receptor ligands in cancer diagnosis and therapy". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1848 (10 Pt B): 2703–2714. doi:10.1016/j.bbamem.2014.08.022. PMID 25173780. <a href="https://doi.org/10.1016%2Fj.bbamem.2014.08.022" target="_blank">https://doi.org/10.1016%2Fj.bbamem.2014.08.022</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Hellewell SB, Bowen WD (September 1990). "A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain". Brain Research. 527 (2): 244–253. doi:10.1016/0006-8993(90)91143-5. PMID 2174717. S2CID 24546226. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Kruse AC (July 2017). "Identification of the gene that codes for the σ2 receptor". Proceedings of the National Academy of Sciences of the United States of America. 114 (27). PNAS (Early edition): 7160–7165. Bibcode:2017PNAS..114.7160A. doi:10.1073/pnas.1705154114. PMC 5502638. PMID 28559337. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502638" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502638</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T, et al. (July 2009). "Identification of cholesterol-regulating genes by targeted RNAi screening". Cell Metabolism. 10 (1): 63–75. doi:10.1016/j.cmet.2009.05.009. PMID 19583955. <a href="https://doi.org/10.1016%2Fj.cmet.2009.05.009" target="_blank">https://doi.org/10.1016%2Fj.cmet.2009.05.009</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Ebrahimi-Fakhari D, Wahlster L, Bartz F, Werenbeck-Ueding J, Praggastis M, Zhang J, et al. (August 2016). "Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells". Human Molecular Genetics. 25 (16): 3588–3599. doi:10.1093/hmg/ddw204. PMC 5179952. PMID 27378690. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179952" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179952</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Ahmed IS, Chamberlain C, Craven RJ (March 2012). "S2R(Pgrmc1): the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling". Expert Opinion on Drug Metabolism & Toxicology. 8 (3): 361–370. doi:10.1517/17425255.2012.658367. PMID 22292588. S2CID 207491179. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Gebreselassie D, Bowen WD (June 2004). "Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes". European Journal of Pharmacology. 493 (1–3): 19–28. doi:10.1016/j.ejphar.2004.04.005. PMID 15189760. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Skuza G (November 2003). "Potential antidepressant activity of sigma ligands" (PDF). Polish Journal of Pharmacology. 55 (6): 923–934. 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