HIV-1 Tat and morphine decrease murine inter-male social interactions and associated oxytocin levels in the prefrontal cortex, amygdala, and hypothalamic paraventricular nucleus

Nass, Sara R.; Lark, Arianna R.S.; Hahn, Yun Kyung; McLane, Virginia D.; Ihrig, Therese M.; Contois, Liangru; Napier, T. Celeste; Knapp, Pamela E.; Hauser, Kurt F.

doi:10.1016/j.yhbeh.2021.105008

Cited by 9 publications

(13 citation statements)

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“…Recent research has focused on OT’s involvement as a neurotransmitter and neuromodulator in the brain and its well-described peripheral effects of triggering uterine contractions and lactation. OT-producing neurons in the hypothalamus innervate brain areas involved in stress, reward, mood, fear, emotion, and drug-seeking behaviours, such as the amygdala, septum, nucleus ambiguous, and nucleus accumbens, which contain OT receptors [ 44 , 45 ]. Numerous animal and human research have implicated OT secretion problems in multiple mental illnesses, including depression, anxiety, schizophrenia, and autism spectrum disorders [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Functional modular networks identify the pivotal genes associated with morphine addiction and potential drug therapies

2023

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Background Chronic morphine usage induces lasting molecular and microcellular adaptations in distinct brain areas, resulting in addiction-related behavioural abnormalities, drug-seeking, and relapse. Nonetheless, the mechanisms of action of the genes responsible for morphine addiction have not been exhaustively studied. Methods We obtained morphine addiction-related datasets from the Gene Expression Omnibus (GEO) database and screened for Differentially Expressed Genes (DEGs). Weighted Gene Co-expression Network Analysis (WGCNA) functional modularity constructs were analyzed for genes associated with clinical traits. Venn diagrams were filtered for intersecting common DEGs (CDEGs). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for functional annotation. Protein–protein interaction network (PPI) and CytoHubba were used to screen for hub genes. Potential treatments for morphine addiction were figured out with the help of an online database. Results Sixty-five common differential genes linked to morphine addiction were identified, and functional enrichment analysis showed that they were primarily involved in ion channel activity, protein transport, the oxytocin signalling pathway, neuroactive ligand-receptor interactions, and other signalling pathways. Based on the PPI network, ten hub genes (CHN2, OLIG2, UGT8A, CACNB2, TIMP3, FKBP5, ZBTB16, TSC22D3, ISL1, and SLC2A1) were checked. In the data set GSE7762, all of the Area Under Curve (AUC) values for the hub gene Receiver Operating Characteristic (ROC) curves were greater than 0.8. We also used the DGIdb database to look for eight small-molecule drugs that might be useful for treating morphine addiction. Conclusions The hub genes are crucial genes associated with morphine addiction in the mouse striatum. The oxytocin signalling pathway may play a vital role in developing morphine addiction.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: Functional modular networks identify the pivotal genes associated with morphine addiction and potential drug therapies

2023

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“…While Tat can disrupt this system ( Paris et al, 2020 ; Salahuddin et al, 2020a , b ), its actions in the amygdala are less well studied. However, we previously found that CRF levels within the amygdala of Tat(+) mice correlate inversely with sociability in mice ( Nass et al, 2021 ), suggesting a role for amygdalar CRF in modulating Tat-induced behavioral deficits.…”

Section: Discussionmentioning

confidence: 96%

“…Doxycycline (DOX)-inducible GFAP-driven tet -on HIV-1 IIIB Tat 1–86 transgenic mice ( Bruce-Keller et al, 2008 ; Nass et al, 2020 , 2021 ) express Tat mRNA and/or protein within 48 h of DOX administration throughout the CNS (e.g., cortex, hippocampus, striatum, and spinal cord) ( Bruce-Keller et al, 2008 ; Fitting et al, 2010 , 2012 ; Carey et al, 2012 ; Dickens et al, 2017 ). Adult (3–5-month-old) male Tat-tg mice ( n = 64) were generated in the vivarium of Virginia Commonwealth University and were housed 3–4 per cage in a temperature- and humidity-controlled, AAALAC-accredited facility, on a 12:12 light:dark cycle.…”

Section: Methodsmentioning

confidence: 99%

“…Morphine sulfate (National Institute on Drug Abuse, Bethesda, MD) was dissolved in sterile saline and mice were administered escalating doses of morphine (10–40 mg/kg, increasing by 10 mg/kg/2 day, s.c.) twice daily (b.i.d.) or saline vehicle for the last 2 weeks of DOX administration as previously described ( Nass et al, 2021 ; Ohene-Nyako et al, 2021 ). Therefore, mice received 10 mg/kg on days 1 and 2, 20 mg/kg on days 3 and 4, 30 mg/kg on days 5 and 6, and 40 mg/kg on days 7–14 or saline starting at 6 weeks following Tat induction ( Figure 1 ).…”

Section: Methodsmentioning

confidence: 99%

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Neurodegeneration Within the Amygdala Is Differentially Induced by Opioid and HIV-1 Tat Exposure

et al. 2022

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Opioid use disorder (OUD) is a critical problem that contributes to the spread of HIV and may intrinsically worsen neuroHIV. Despite the advent of combined antiretroviral therapies (cART), about half of persons infected with HIV (PWH) experience cognitive and emotional deficits that can be exacerbated by opioid abuse. HIV-1 Tat is expressed in the central nervous system (CNS) of PWH on cART and is thought to contribute to neuroHIV. The amygdala regulates emotion and memories associated with fear and stress and is important in addiction behavior. Notwithstanding its importance in emotional saliency, the effects of HIV and opioids in the amygdala are underexplored. To assess Tat- and morphine-induced neuropathology within the amygdala, male Tat transgenic mice were exposed to Tat for 8 weeks and administered saline and/or escalating doses of morphine twice daily (s.c.) during the last 2 weeks of Tat exposure. Eight weeks of Tat exposure decreased the acoustic startle response and the dendritic spine density in the basolateral amygdala, but not the central nucleus of the amygdala. In contrast, repeated exposure to morphine alone, but not Tat, increased the acoustic startle response and whole amygdalar levels of amyloid-β (Aβ) monomers and oligomers and tau phosphorylation at Ser396, but not neurofilament light chain levels. Co-exposure to Tat and morphine decreased habituation and prepulse inhibition to the acoustic startle response and potentiated the morphine-induced increase in Aβ monomers. Together, our findings indicate that sustained Tat and morphine exposure differentially promote synaptodendritic degeneration within the amygdala and alter sensorimotor processing.

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“…Starting at day 43 (week 6) of DOX administration, mice were administered escalating, subcutaneous (s.c.) doses of morphine sulfate (Drug Supply Program, National Institute on Drug Abuse, Bethesda, MD) dissolved in sterile saline (10–40 mg/kg administered twice daily (b.i.d. ), increasing by 10 mg/kg at 2-day intervals) or saline until the end of the experiment (2 weeks total) as previously described ( Figure 1 [ 51 , 65 ]). All solutions were warmed to room temperature before being administered at a volume of 10 µL/g body weight.…”

Section: Methodsmentioning

confidence: 99%

Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure

Nass

Hahn

Ohene‐Nyako

et al. 2023

Viruses

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Opioid use disorder (OUD) and HIV are comorbid epidemics that can increase depression. 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—activities 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.

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HIV-1 Tat and morphine decrease murine inter-male social interactions and associated oxytocin levels in the prefrontal cortex, amygdala, and hypothalamic paraventricular nucleus

Cited by 9 publications

References 131 publications

RETRACTED ARTICLE: Functional modular networks identify the pivotal genes associated with morphine addiction and potential drug therapies

RETRACTED ARTICLE: Functional modular networks identify the pivotal genes associated with morphine addiction and potential drug therapies

Neurodegeneration Within the Amygdala Is Differentially Induced by Opioid and HIV-1 Tat Exposure

Depressive-like Behavior Is Accompanied by Prefrontal Cortical Innate Immune Fatigue and Dendritic Spine Losses after HIV-1 Tat and Morphine Exposure

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