Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts

Peer reviewe

Strain and cocaine-induced differential opioid gene expression may predispose Lewis but not Fischer rats to escalate cocaine self-administration.

The aim of the present study was to investigate alterations in gene expression of opioid system components induced by extended access (18 h) cocaine self-administration and to determine the impact of genetic background in the vulnerability to escalate cocaine intake. Comparing two inbred rat strains, we previously reported that Lewis rats progressively escalated cocaine consumption compared to Fischer rats, in a new translational model of intravenous cocaine self-administration, which included 14 sessions of 18-h operant sessions in which rats were allowed to select the cocaine unit dose to self-administer. We compare here Fischer and Lewis rats in the gene expression of endogenous opioid peptides (Pomc, Penk, Pdyn) and cognate receptors (Oprm, Oprk and Oprd) in reward-related brain regions, after exposure to either cocaine self-administration or yoked-saline, in the aforementioned translational paradigm. We performed a correlation analysis between the mRNA level, found in the Dorsal Striatum (DS), Nucleus accumbens (NAcc) shell and core respectively, and individual cocaine intake. Our findings show that the gene expression of all the aforementioned opioid genes exhibit strain-dependent differences in the DS, in absence of cocaine exposure. Also, different strain-specific cocaine-induced mRNA expression of Oprm and Oprk was found in DS. Only few differences were found in the ventral parts of the striatum. Moreover, gene expression level of Pdyn, Penk, Oprk, and Oprm in the DS was significantly correlated with cocaine intake only in Fischer rats. Overall, these data shed light on potential genetic differences which may predispose of subjects to initiate and escalate cocaine consumption

Study of the Photocatalytic Properties of Ni-Doped Nanotubular Titanium Oxide

Nanotubular titanium oxide is widely known as a prospective semiconductor photocatalyst for the process of water splitting. Its photoelectrochemical (PEC) efficiency can be improved by doping with 3d metal. In this work, the synthesis of nanotubular titanium oxide (NTO) was carried out by anodizing titanium substrates using two doping techniques. First, Ni-doped TiO2 was obtained by immersion in Ni salt solution; second, an ethylene glycol-based fluoride electrolyte containing Ni2+ ions solution was used. The obtained samples were analyzed using SEM, XRD, and photoelectrochemical methods. The produced Ni-doped NTO exhibited photocatalytic activity twice as high as that of nondoped NTO. Additionally, it was found that the immersion technique initiated a shift of the incident photon to converted electron (IPCE) spectra to the visible part of the spectrum

Expression of Ephrin Receptors and Ligands in Postmortem Brains of HIV-Infected Subjects With and Without Cognitive Impairment

Despite the successes of combination antiretroviral therapy, HIV-associated neurocognitive disorders persist in many infected individuals. Earlier studies showed that neurocognitive impairment was associated with glutamate toxicity and synaptodendritic damage. We examined alterations in expression of four ephrin genes that are involved in synapse formation and recruitment of glutamate receptors to synapses, in the caudate and anterior cingulate in postmortem brain of cognitively characterized HIV-infected subjects, along with expression of neuronal and astroglial/macroglial markers. Postmortem tissues of HIV-infected and control subjects were obtained from the Manhattan HIV Brain Bank. HIV-infected subjects underwent neurocognitive assessment prior to death. Quantification of mRNA of genes of chemokine receptors and chemokines (CCR5, CXCR4, CCL2), astroglial/microglial markers (GFAP, CD163, CD68), the neuronal marker SNAP25, ephrin receptors EPHA4 and EPHB2, and ephrin ligands EFNB1 and EFNB2 was performed using SYBR Green RT-PCR. Proinflammatory chemokine and glial/macrophage mRNA levels in both regions were significantly greater in HIV+ than in HIV- subjects. Levels of EPHA4 and EFNB2 mRNA in the caudate, and EPHB2 mRNA in anterior cingulate were significantly lower in HIV+ subjects (p < 0.002, p < 0.02, p < 0.05, respectively). These transcripts also showed correlations with immune status and cognitive function within the HIV-infected group. Decreased levels of EFNB2 mRNA in the caudate correlated with lower CD4 counts (P < 0.05). Cognitive associations were limited to the cingulate, where decreased levels of EPHB2 mRNA were associated with better global cognitive status. Decreased cingulate expression of EPHB2 may represent a compensatory mechanism minimizing excitotoxic injury in the face of chronic inflammation

Oxycodone Self-Administration Induces Alterations in Expression of Integrin, Semaphorin and Ephrin Genes in the Mouse Striatum

Oxycodone is one a commonly used medication for pain, and is also a widely abused prescription opioid, like other short-acting MOPr agonists. Neurochemical and structural adaptations in brain following chronic MOPr-agonist administration are thought to underlie pathogenesis and persistence of opiate addiction. Many axon guidance molecules, such as integrins, semaphorins, and ephrins may contribute to oxycodone-induced neuroadaptations through alterations in axon-target connections and synaptogenesis, that may be implicated in the behaviors associated with opiate addiction. However, little is known about this important area. The aim of this study is to investigate alterations in expression of selected integrin, semaphorin, ephrins, netrin, and slit genes in the nucleus accumbens (NAc) and caudate putamen (CPu) of mice following extended 14-day oxycodone self-administration (SA), using RNAseq.Methods: Total RNA from the NAc and CPu were isolated from adult male C57BL/6J mice within 1 h after the last session of oxycodone in a 14-day self-administration paradigm (4h/day, 0.25 mg/kg/infusion, FR1) or from yoked saline controls. Gene expressions were examined using RNA sequencing (RNA-Seq) technology. RNA-Seq libraries were prepared using Illumina's TruSeq® Stranded Total RNA LT kit. The reads were aligned to the mouse reference genome (version mm10) using STAR. DESeq2 was applied to the counts of protein coding genes to estimate the fold change between the treatment groups. False Discovery Rate (FDR) q &lt; 0.1 were used to select genes that have a significant expression change. For selection of a subset of genes related to axon guidance pathway, REACTOME was used.Results: Among 38 known genes of the integrin, semaphorin, and ephrin gene families, RNA-seq data revealed up-regulation of six genes in the NAc: heterodimer receptor, integrins Itgal, Itgb2, and Itgam, and its ligand semaphorin Sema7a, two semaphorin receptors, plexins Plxnd1 and Plxdc1. There was down-regulation of eight genes in this region: two integrin genes Itga3 and Itgb8, semaphorins Sema3c, Sema4g, Sema6a, Sema6d, semaphorin receptor neuropilin Nrp2, and ephrin receptor Epha3. In the CPu, there were five differentially expressed axon guidance genes: up-regulation of three integrin genes, Itgal, Itgb2, Itga1, and down-regulation of Itga9 and ephrin Efna3 were thus observed. No significant alterations in expression of Netrin-1 or Slit were observed.Conclusion: We provide evidence for alterations in the expression of selective axon guidance genes in adult mouse brain following chronic self-administration of oxycodone. Further examination of oxycodone-induced changes in the expression of these specific axon guidance molecules and integrin genes in relation to behavior may provide new insights into development of addiction to oxycodone

Expression of Ephrin Receptors and Ligands in Postmortem Brains of HIV-Infected Subjects With and Without Cognitive Impairment

Despite the successes of combination antiretroviral therapy, HIV-associated neurocognitive disorders persist in many infected individuals. Earlier studies showed that neurocognitive impairment was associated with glutamate toxicity and synaptodendritic damage. We examined alterations in expression of four ephrin genes that are involved in synapse formation and recruitment of glutamate receptors to synapses, in the caudate and anterior cingulate in postmortem brain of cognitively characterized HIV-infected subjects, along with expression of neuronal and astroglial/macroglial markers. Postmortem tissues of HIV-infected and control subjects were obtained from the Manhattan HIV Brain Bank. HIV-infected subjects underwent neurocognitive assessment prior to death. Quantification of mRNA of genes of chemokine receptors and chemokines (CCR5, CXCR4, CCL2), astroglial/microglial markers (GFAP, CD163, CD68), the neuronal marker SNAP25, ephrin receptors EPHA4 and EPHB2, and ephrin ligands EFNB1 and EFNB2 was performed using SYBR Green RT-PCR. Proinflammatory chemokine and glial/macrophage mRNA levels in both regions were significantly greater in HIV+ than in HIV- subjects. Levels of EPHA4 and EFNB2 mRNA in the caudate, and EPHB2 mRNA in anterior cingulate were significantly lower in HIV+ subjects (p < 0.002, p < 0.02, p < 0.05, respectively). These transcripts also showed correlations with immune status and cognitive function within the HIV-infected group. Decreased levels of EFNB2 mRNA in the caudate correlated with lower CD4 counts (P < 0.05). Cognitive associations were limited to the cingulate, where decreased levels of EPHB2 mRNA were associated with better global cognitive status. Decreased cingulate expression of EPHB2 may represent a compensatory mechanism minimizing excitotoxic injury in the face of chronic inflammation

Polymorphisms of the Kappa Opioid Receptor and Prodynorphin Genes: HIV Risk and HIV Natural History

Objective: Studies indicate cross-desensitization between opioid receptors (eg, kappa opioid receptor, OPRK1) and chemokine receptors (eg, CXCR4) involved in HIV infection. Whether gene variants of OPRK1 and its ligand, prodynorphin (PDYN), influence the outcome of HIV therapy was tested. Methods: Three study points, admission to the Women's Interagency HIV Study, initiation of highly active antiretroviral therapy (HAART), and the most recent visit, were chosen for analysis as crucial events in the clinical history of the HIV patients. Regression analyses of 17 variants of OPRK1 and 11 variants of PDYN with change of viral load (VL) and CD4 count between admission and initiation of HAART and initiation of HAART to the most recent visit to Women's Interagency HIV Study were performed in 598 HIV+ subjects, including African Americans, Hispanics, and Whites. Association with HIV status was done in 1009 subjects. Results: Before HAART, greater VL decline (improvement) in carriers of PDYN IVS3+189C>T and greater increase of CD4 count (improvement) in carriers of OPRK -72C>T were found in African Americans. Also, greater increase of CD4 count in carriers of OPRK1 IVS2+7886A>G and greater decline of CD4 count (deterioration) in carriers of OPRK1 - 21205G>A were found in Whites. After HAART, greater decline of VL in carriers of OPRK1 IVS2+ 2225G. A and greater increase of VL in carriers of OPRK1 IVS2+ 10658G. T and IVS2+ 10963A. G were found in Whites. Also, a lesser increase of CD4 count was found in Hispanic carriers of OPRK1 IVS2 + 2225G. A. Conclusions: OPRK1 and PDYN polymorphisms may alter severity of HIV infection and response to treatment