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Currently, there are no defined therapeutic protocols to manage psychosis in TLE patients, as antipsychotic agents may induce epileptic seizures and are associated with severe side effects and pharmacokinetic and pharmacodynamic interactions with antiepileptic drugs. Thus, novel treatment strategies are necessary. Several lines of evidence suggest that hippocampal hyperactivity is central to the pathology of both TLE and psychosis; therefore, restoring hippocampal activity back to normal levels may be a novel therapeutic approach for treating psychosis in TLE. In rodent models, increased activity in the ventral hippocampus (vHipp) results in aberrant dopamine system function, which is thought to underlie symptoms of psychosis. Indeed, we have previously demonstrated that targeting \u03b15-containing \u03b3-aminobutyric acid receptors (\u03b15GABAARs), an inhibitory receptor abundant in the hippocampus, with positive allosteric modulators (PAMs), can restore dopamine system function in rodent models displaying hippocampal hyperactivity. Thus, we posited that \u03b15-PAMs may be beneficial in a model used to study TLE. Here, we demonstrate that pilocarpine-induced TLE is associated with increased VTA dopamine neuron activity, an effect that was completely reversed by intra-vHipp administration of GL-II-73, a selective \u03b15-PAM. Further, pilocarpine did not alter the hippocampal \u03b15GABAAR expression or synaptic localization that may affect the efficacy of \u03b15-PAMs. Taken together, these results suggest augmenting \u03b15GABAAR function as a novel therapeutic modality for the treatment of psychosis in TLE.<\/jats:p>","DOI":"10.3390\/ijms241411588","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T00:47:38Z","timestamp":1689727658000},"page":"11588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["GL-II-73, a Positive Allosteric Modulator of \u03b15GABAA Receptors, Reverses Dopamine System Dysfunction Associated with Pilocarpine-Induced Temporal Lobe Epilepsy"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8449-7717","authenticated-orcid":false,"given":"Alexandra M.","family":"McCoy","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USA"},{"name":"South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D.","family":"Prevot","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dishary","family":"Sharmin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5512-3022","authenticated-orcid":false,"given":"James M.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne L.","family":"Sibille","sequence":"additional","affiliation":[{"name":"Campbell Family Mental Health Research Institute of CAMH, Toronto, ON M5S 2S1, Canada"},{"name":"Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada"},{"name":"Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5T 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Lodge","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Center for Biomedical Neuroscience, UT Health San Antonio, San Antonio, TX 78229, USA"},{"name":"South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.yebeh.2011.11.004","article-title":"Neuroimaging of frontal\u2013limbic dysfunction in schizophrenia and epilepsy-related psychosis: Toward a convergent neurobiology","volume":"23","author":"Butler","year":"2012","journal-title":"Epilepsy Behav."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1176\/appi.neuropsych.12120403","article-title":"Risk Factors for Psychosis Secondary to Temporal Lobe Epilepsy: A Systematic Review","volume":"26","author":"Irwin","year":"2014","journal-title":"J. Neuropsychiatry Clin. 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