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HIV and the viral protein Tat can directly induce neuronal injury within reward and emotionality brain circuitry, including the prefrontal cortex (PFC). Such damage involves both excitotoxic mechanisms and more indirect pathways through neuroinflammation, both of which can be worsened by opioid co-exposure. To assess whether excitotoxicity and\/or neuroinflammation might drive depressive behaviors in persons infected with HIV (PWH) and those who use opioids, male mice were exposed to HIV-1 Tat for eight weeks, given escalating doses of morphine during the last two weeks, and assessed for depressive-like behavior. Tat expression decreased sucrose consumption and adaptability, whereas morphine administration increased chow consumption and exacerbated Tat-induced decreases in nesting and burrowing\u2014activities associated with well-being. Across all treatment groups, depressive-like behavior correlated with increased proinflammatory cytokines in the PFC. Nevertheless, supporting the theory that innate immune responses adapt to chronic Tat exposure, most proinflammatory cytokines were unaffected by Tat or morphine. Further, Tat increased PFC levels of the anti-inflammatory cytokine IL-10, which were exacerbated by morphine administration. Tat, but not morphine, decreased dendritic spine density on layer V pyramidal neurons in the anterior cingulate. Together, our findings suggest that HIV-1 Tat and morphine differentially induce depressive-like behaviors associated with increased neuroinflammation, synaptic losses, and immune fatigue within the PFC.<\/jats:p>","DOI":"10.3390\/v15030590","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T02:30:35Z","timestamp":1676946635000},"page":"590","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1868-1257","authenticated-orcid":false,"given":"Sara R.","family":"Nass","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun K.","family":"Hahn","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Neurobiology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1004-3568","authenticated-orcid":false,"given":"Michael","family":"Ohene-Nyako","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia D.","family":"McLane","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Imad","family":"Damaj","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Leroy R.","family":"Thacker","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela E.","family":"Knapp","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA"},{"name":"Department of Anatomy and Neurobiology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0709, USA"},{"name":"Institute for Drug and Alcohol Studies, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt F.","family":"Hauser","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0613, USA"},{"name":"Department of Anatomy and Neurobiology, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0709, USA"},{"name":"Institute for Drug and Alcohol Studies, Medical College of Virginia (MCV) Campus, Virginia Commonwealth University, Richmond, VA 23298-0059, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1097\/YCO.0000000000000712","article-title":"The opioid overdose crisis as a global health challenge","volume":"34","author":"Krausz","year":"2021","journal-title":"Curr. 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