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Pharmacol."],"abstract":"<jats:p>Individuals with substance use disorder are at a higher risk of contracting HIV and progress more rapidly to AIDS as drugs of abuse, such as cocaine, potentiate the neurotoxic effects of HIV-associated proteins including, but not limited to, HIV-1 trans-activator of transcription (Tat) and the envelope protein Gp120. Neurotoxicity and neurodegeneration are hallmarks of HIV-1-associated neurocognitive disorders (HANDs), which are hypothesized to occur secondary to excitotoxicity from NMDA-induced neuronal calcium dysregulation, which could be targeted with NMDA antagonist drugs. Multiple studies have examined how Gp120 affects calcium influx and how cocaine potentiates this influx; however, they mostly focused on single cells and did not analyze effects in neuronal and vascular brain networks. Here, we utilize a custom multi-wavelength imaging platform to simultaneously study the neuronal activity (detected using genetically encoded Ca<jats:sup>2+<\/jats:sup>indicator, GcaMP6f, expressed in neurons) and hemodynamic changes (measured by total hemoglobin and oxygenated hemoglobin within the tissue) in the prefrontal cortex (PFC) of HIV-1 Tg rats in response to cocaine and evaluate the effects of the selective NMDA antagonist drug memantine on cocaine and HIV neurotoxicity compared to those of non-HIV-1 Tg animals (controls). Our results show that memantine improved cocaine-induced deficit in cerebral blood volume while also attenuating an abnormal increase of the neuronal calcium influx and influx duration in both control rats and HIV-1 Tg rats. Cocaine-induced neuronal and hemodynamic dysregulations were significantly greater in HIV-1 Tg rats than in control rats. With memantine pretreatment, HIV-1 Tg rats showed attenuated cocaine\u2019s effects on neuronal and hemodynamic responses, with responses similar to those observed in control rats. These imaging results document an enhancement of neuronal Ca<jats:sup>2+<\/jats:sup>influx, hypoxemia, and ischemia with cocaine in the PFC of HIV-1 Tg rats that were attenuated by memantine pretreatment. Thus, the potential utility of memantine in the treatment of HAND and of cocaine-induced neurotoxicity deserves further investigation.<\/jats:p>","DOI":"10.3389\/fphar.2022.895006","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T09:10:58Z","timestamp":1653469858000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Memantine Attenuates Cocaine and neuroHIV Neurotoxicity in the Medial Prefrontal Cortex"],"prefix":"10.3389","volume":"13","author":[{"given":"Congwu","family":"Du","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueming","family":"Hua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin","family":"Clare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kicheon","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig P.","family":"Allen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nora D.","family":"Volkow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiu-Ti","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingtian","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/j.biopsych.2009.12.023","article-title":"N-methyl-D-aspartic Acid Receptors on Striatal Neurons Are Essential for Cocaine Cue Reactivity in Mice","volume":"67","author":"Agatsuma","year":"2010","journal-title":"Biol. 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