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. 2022 Mar 24;14(4):669.
doi: 10.3390/v14040669.

Escalated (Dependent) Oxycodone Self-Administration Is Associated with Cognitive Impairment and Transcriptional Evidence of Neurodegeneration in Human Immunodeficiency Virus (HIV) Transgenic Rats

Yu Fu  1   2 , Irene Lorrai  1 , Barry Zorman  3 , Daniele Mercatelli  4 , Chase Shankula  1 , Jorge Marquez Gaytan  1 , Celine Lefebvre  1   5 , Giordano de Guglielmo  6 , Hyunjae Ryan Kim  3 , Pavel Sumazin  3 , Federico M Giorgi  4 , Vez Repunte-Canonigo  1 , Pietro Paolo Sanna  1
Affiliations

Escalated (Dependent) Oxycodone Self-Administration Is Associated with Cognitive Impairment and Transcriptional Evidence of Neurodegeneration in Human Immunodeficiency Virus (HIV) Transgenic Rats

Yu Fu et al. Viruses. .

Abstract

Substance use disorder is associated with accelerated disease progression in people with human immunodeficiency virus (HIV; PWH). Problem opioid use, including high-dose opioid therapy, prescription drug misuse, and opioid abuse, is high and increasing in the PWH population. Oxycodone is a broadly prescribed opioid in both the general population and PWH. Here, we allowed HIV transgenic (Tg) rats and wildtype (WT) littermates to intravenously self-administer oxycodone under short-access (ShA) conditions, which led to moderate, stable, "recreational"-like levels of drug intake, or under long-access (LgA) conditions, which led to escalated (dependent) drug intake. HIV Tg rats with histories of oxycodone self-administration under LgA conditions exhibited significant impairment in memory performance in the novel object recognition (NOR) paradigm. RNA-sequencing expression profiling of the medial prefrontal cortex (mPFC) in HIV Tg rats that self-administered oxycodone under ShA conditions exhibited greater transcriptional evidence of inflammation than WT rats that self-administered oxycodone under the same conditions. HIV Tg rats that self-administered oxycodone under LgA conditions exhibited transcriptional evidence of an increase in neuronal injury and neurodegeneration compared with WT rats under the same conditions. Gene expression analysis indicated that glucocorticoid-dependent adaptations contributed to the gene expression effects of oxycodone self-administration. Overall, the present results indicate that a history of opioid intake promotes neuroinflammation and glucocorticoid dysregulation, and excessive opioid intake is associated with neurotoxicity and cognitive impairment in HIV Tg rats.

Keywords: AIDS; cognitive impairment; neuroHIV; neuroinflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Gene expression profiling in the mPFC in HIV Tg and WT rats that self-administered oxycodone under nondependent (ShA) and dependent (LgA) conditions. (A) Volcano plot of changes in gene expression in the mPFC in HIV Tg rats with a history of oxycodone self-administration under ShA conditions compared with oxycodone-self-administering WT rats under the same conditions. The plots show significance (Log10 of p value) vs. fold-change (Log2) on the y and x axes, respectively. Genes that significantly increased in HIV Tg rats vs. WT rats with oxycodone self-administration under ShA conditions are indicated in red. Genes that significantly decreased are indicated in blue. (B) Volcano plot of changes in gene expression in the mPFC in HIV Tg rats with a history of oxycodone self-administration under LgA conditions compared with oxycodone-self-administering WT rats under the same conditions. Genes that significantly increased in HIV Tg rats vs. WT rats that self-administered oxycodone under LgA conditions are indicated in red. Genes that significantly decreased are indicated in blue. (C) Volcano plot of changes in gene expression in the mPFC in HIV Tg rats with a history of oxycodone self-administration under LgA conditions compared with oxycodone-naive HIV Tg rats and (D) volcano plot of changes in gene expression in the mPFC in WT rats with a history of oxycodone self-administration under LgA conditions compared with oxycodone-naive WT rats. (E) Pathway analysis by GSEA [60] of HIV Tg rats vs. WT rats that self-administered oxycodone under ShA conditions. Transcriptional evidence of an increase in neuroinflammation was seen in HIV Tg rats compared with WT rats that self-administered oxycodone under the same conditions. (F) Pathway analysis of HIV Tg rats vs. WT rats that self-administered oxycodone under LgA conditions. Transcriptional evidence of an increase in neuronal injury and neurodegeneration was seen in HIV Tg rats compared with WT rats under the same conditions. NES, normalized enrichment score [60].
Figure 3
Figure 3
Differential expression of the glucocorticoid-responsive gene Tsc22d3 (Gilz) by histories of nondependent (ShA) and dependent (LgA) oxycodone self-administration in HIV Tg rats and WT rats. (A) RNA-sequencing expression of the glucocorticoid-responsive gene Tsc22d3 (Gilz) increased in both HIV Tg rats and WT rats with histories of oxycodone self-administration under ShA conditions compared with their respective oxycodone-naive controls, which was indicative of dysregulation of glucocorticoid-dependent gene expression associated with oxycodone self-administration. Tsc22d3 expression did not increase in HIV Tg rats or WT rats with histories of oxycodone self-administration under LgA conditions, consistent with adaptations that occur under conditions of chronic elevations of glucocorticoids [82,83] (F2,34 = 21.91, p < 0.0001, n = 6–7/group). (B) Consistent results were obtained by RT-PCR (F2,36 = 19.64, p < 0.0001, n = 7–8 /group). * p < 0.05, ** p < 0.01, *** p < 0.001 (Newman–Keuls post hoc test).
Figure 1
Figure 1
Intravenous oxycodone self-administration in HIV Tg rats and WT rats under nondependent (short access (ShA)) and dependent (long access (LgA)) conditions. (A) HIV Tg rats and WT littermates self-administering oxycodone under a fixed-ratio 1 (FR1) schedule under short-access (ShA) conditions in 1-h daily sessions or under long-access (LgA) conditions in 12-h daily sessions. HIV Tg rats and WT littermates escalated oxycodone self-administration under LgA conditions. Oxycodone intake did not differ between HIV Tg and WT rats under either ShA or LgA conditions. * p < 0.05, ** p < 0.005, *** p < 0.0005, **** p < 0.0001 vs. Session 1 (Newman–Keuls post hoc test). (B) Following a period of enforced abstinence to model the intermittent pattern of opioid abuse in humans, HIV Tg and WT rats both under ShA and LgA conditions promptly resumed their previous levels of self-administration, which did not differ between genotypes. (C) Oxycodone self-administration under ShA and LgA conditions did not differ between genotypes after a second period of enforced abstinence. (D) The pattern of oxycodone self-administration in HIV Tg and WT rats under LgA conditions was highly reproducible and closely replicated in an independent set of rats. * p < 0.05, ** p < 0.005, *** p < 0.0005, **** p < 0.0001 vs. Session 1 (Newman–Keuls post hoc test). (E) Following a period of enforced abstinence, rats of both genotypes promptly resumed their previous levels of self-administration, which did not differ between genotypes. (F) HIV Tg rats with a history of escalated oxycodone self-administration under LgA conditions performed significantly worse than WT littermates in the NOR task during protracted withdrawal. HIV Tg rats vs. naive HIV Tg rats: * p < 0.05; HIV Tg rats vs. naive WT rats: * p < 0.05; HIV Tg rats vs. WT rats: ** p < 0.005; Newman–Keuls post hoc test.
Figure 4
Figure 4
Transcriptional evidence of an increase in neuroinflammation in HIV Tg rats that self-administered oxycodone under nondependent (short access (ShA)) conditions. Pathway analysis by GSEA provided evidence of (A,B) broad immune activation and (C) the induction of cytokine signaling, including (D) interferon (IFN) signaling, (E) Toll signaling, (F) TGFβ, (G) SHP2 signaling, and (H) complement and coagulation cascades. Each bar represents a gene in the gene set [60]. HIV ND, HIV Tg rats that self-administered oxycodone under nondependent (ShA) conditions; WT ND, wildtype rats that self-administered oxycodone under nondependent conditions. NES = normalized enrichment score [60].
Figure 5
Figure 5
Transcriptional evidence of increases in neuronal injury and neurodegeneration in HIV Tg rats that self-administered oxycodone under dependent (LgA) conditions. Representative pathways that were differentially activated by GSEA are indicative of an increase in the expression of (A) interferon (IFN) signaling and (B) complement (which has been implicated in increases in inflammation and neurodegeneration [88]) and the broad downregulation of (C) neuronal genes, including genes that are involved in (D) neuronal communication, (E) neural plasticity, and (F,G) signaling and (H) genes that are involved in neurodegenerative conditions (e.g., Alzheimer’s disease) and (I,J) trophism. Each bar represents a gene in the gene set [60]. NES, normalized enrichment score [60]; HIV D, HIV Tg rats that self-administered oxycodone under dependent (long access (LgA)) conditions; WT D, wildtype rats that self-administered oxycodone under dependent conditions. NES = normalized enrichment score [60].
Figure 6
Figure 6
Differential regulation of selected pathways by histories of nondependent (ShA) and dependent (LgA) oxycodone self-administration in HIV Tg rats and WT rats. The figure shows the differential regulation of gene sets that are relevant to neurodegeneration in HIV Tg rats and WT rats with histories of nondependent (ShA) and dependent (LgA) oxycodone self-administration. (A) Glucocorticoid regulated genes showed greater adaptations in HIV Tg rats with a history of dependent (LgA) oxycodone self-administration. (B) Nfat3 regulated genes, (C) genes that are involved in neuronal communication, including synaptodendritic genes, (D) genes that are related to signaling, such as DARPP32 regulated events, and (E) genes that are related to axonal function were downregulated in HIV Tg rats with a history of dependent (LgA) oxycodone self-administration. * p < 0.05, ** p < 0.01, vs. oxycodone-naive control rats of the respective genotype. NES = normalized enrichment score [60].
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