Adaptations in nucleus accumbens neuron subtypes mediate negative affective behaviors in fentanyl abstinence
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE209969 | GEO | 2022/07/31
REPOSITORIES: GEO
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Project description:We used RNAseq to evaluate baseline expression of NPAS+ VP translatomes in comparison to bulk VP translatomes.
2022-11-28 | GSE218580 | GEO
Project description:An increase in opioid-overdose deaths was evident before the COVID-19 pandemic, and has escalated since its onset. Fentanyl, a highly potent synthetic opioid, is the primary driver of these recent trends. The current study used two inbred mouse strains, C57BL/6 J and A/J, to investigate the genetics of behavioral responses to fentanyl. Mice were tested for conditioned place preference and fentanyl-induced locomotor activity. C57BL/6J mice formed a conditioned place preference to fentanyl injections and fentanyl increased their activity. Neither effect was noted in A/J mice. We conducted RNA-sequencing on the nucleus accumbens of mice used for fentanyl-induced locomotor activity. Surprisingly, we noted few differentially expressed genes using treatment as the main factor. However many genes differed between strains. We validated differences in two genes: suppressor APC domain containing 1 (Sapcd1) and Glyoxalase 1 (Glo1), with quantitative PCR on RNA from the nucleus accumbens and prefrontal cortex. In both regions A/J mice had significantly higher expression of both genes than did C57BL/6 J. In prefrontal cortex, fentanyl treatment decreased Glo1 mRNA. Glyoxalase 1 catalyzes the detoxification of reactive alpha-oxoaldehydes such as glyoxal and methylglyoxal, is associated with anxiety and activity levels, and its inhibition reduces alcohol intake. We suggest that future studies assess the ability of Glo1 and related metabolites to modify opioid intake.
2023-01-10 | GSE222569 | GEO
Project description:Background: Opioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown. Methods: Male (n=13) and female (n=12) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h self-administration sessions. After two weeks of this selfadministration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined. Results: Prior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited similar increases in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with a greater number of differentially expressed genes in the NAc and VTA of opioidwithdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females. Conclusions: These results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.
2021-05-06 | GSE173959 | GEO
Project description:The US is in the midst of a major drug epidemic fueled in large part by the widespread recreational use of syntheticopioids such as fentanyl. we evaluated the impact of fentanyl using in cell lines that replicate infectious viruses. RNAseq identified a number of hepatocyte genes that were differentially regulated by fentanyl, including those related to apoptosis, the antiviral / interferon response, chemokine signaling, and NFkB signaling.
2021-04-21 | GSE167922 | GEO
Project description:Fentanyl enhanced expression of CXCR4 and CCR5 protein levels and viral expression in a dose-dependent manner in multiple HIV-susceptible and HIV-infected cell lines. Multiple genes associated with apoptosis, antiviral / interferon response, chemokine. signaling, and NFκB signaling were differentially regulated by fentanyl. Thus fentanyl impacts HIV replication and chemokine co-receptor expression in HIV-susceptible and HIV-infected lymphocyte cell lines suggesting that opioid use may increase the likelihood of transmission to others and accelerate disease progression.
2022-10-20 | GSE216124 | GEO
Project description:The illicit use of synthetic opioids such as fentanyl has led to a serious public health crisis in the United States. People with opioid use disorder are more likely to contract infections such as HIV and viral hepatitis. While several drugs of abuse are known to enhance viral replication and to suppress immunologic responses, the effects of synthetic opioids on HIV pathogenesis have not been investigated thoroughly. Thus, we examined the impact of fentanyl on HIV-susceptible and HIV-infected cell types and chemokine receptor expression in vitro. TZM-bl and HIV-infected lymphocyte cells were incubated with fentanyl at concentrations of 1 ng, 100 ng, and 10 ug. Expression levels of the CXCR4 and CCR5 chemokine receptors were measured in cell lysates, and HIV p24 antigen was quantified in culture supernatants by ELISA. HIV proviral DNA was quantified in cells using SYBR RT-PCR targeting the pol gene. Cell viability in the presence of drug was detected by the MTT Cell Proliferation Assay. RNA-seq and miRNAseq was performed to characterize cellular gene regulation in the presence of fentanyl. Fentanyl enhanced expression of CXCR4 and CCR5 protein levels in a dose-dependent manner in HIV-susceptible and HIV-infected cells. Similarly, fentanyl induced viral expression in HIV-exposed TZM-bl cells and in multiple HIV-infected lymphocyte cell lines. Multiple genes associated with apoptosis, antiviral / interferon response, chemokine signaling, and NFκB signaling were differentially regulated by fentanyl. These data demonstrate that the synthetic opioid fentanyl impacts HIV replication and chemokine co-receptor expression in HIV-susceptible and HIV-infected cells. Increased virus levels also suggest that opioid use may increase the likelihood of transmission to others and accelerate disease progression.
2022-10-19 | GSE216044 | GEO
Project description:It remains poorly understood what and how changes in brain activity from chronic fentanyl use influences the respective behavioral outcome. We examined the functional and molecular changes to cortical neural network activity following sub-chronic exposure to two fentanyl concentrations, a low (0.01 µM) and high (10 µM) dose from primary rat co-cultures, containing cortical neurons, astrocytes, and oligodendrocyte-lineage cell.
2022-08-31 | GSE207606 | GEO
Project description:Use of addictive substances often creates powerful and enduring associations with external cues that act as relapse triggers in individuals recovering from a substance use disorder (SUD). In the reward-associated brain region, the nucleus accumbens (NAc), drug use or drug-associated cue exposure activates a subset of D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), which typically promotes drug seeking, and a smaller subset of D2 dopamine receptor-expressing MSNs (D2-MSNs), which typically opposes drug seeking. The activity-regulated transcription factor, Neuronal PAS Domain Protein 4 (NPAS4), is activated in a small subset of NAc neurons during cocaine conditioning, and NAc NPAS4 is required for drug-context memories. Using a new Npas4-TRAP mouse combined with chemogenetics, we found that the during cocaine conditioning, the NPAS4-positive ensemble is required for drug-context associations. Single-cell transcriptomic analyses and in situ hybridization of NAc tissues from drug-conditioned mice revealed that NPAS4 is expressed predominantly in MSNs, and using cell type-specific molecular genetic approaches, we found that NPAS4 in D2-MSNs, but not D1-MSNs, was required for both drug-context associations and cue-reinstated cocaine seeking. Similarly, NPAS4 in NAc D2-MSNs, but not D1-MSNs, blocked cocaine experience-dependent strengthening of glutamatergic prefrontal cortical (PFC) inputs onto D2-MSNs. Analysis of differential gene expression in D2-MSNs revealed that NPAS4 and cocaine conditioning influence a gene expression program associated with synapses, dendrites, neuronal projections, dopamine, and cocaine. Together, our data reveal that NPAS4 functions during active cocaine use to maintain the imbalance of D1-MSN:D2-MSN activation and cue-induced drug seeking by suppressing excitatory drive onto relapse-opposing NAc D2-MSN circuits.
2023-08-31 | GSE210850 | GEO
Project description: Not available
| S-EPMC3674635 | biostudies-literature
Project description:Using bulk RNAseq, we explored transcriptomic landscape of three reward areas - PrL, NAc, VTA and two sensory areas -S1, VBT in perinatal fentanyl exposed juvenile mice
2023-05-08 | GSE231981 | GEO