Dataset Information

Behavioral and transcriptomic markers of susceptibility to escalate fentanyl intake.

ABSTRACT: Background: The “loss of control” over drug consumption, known as escalation of intake in opioid use disorder (OUD), is well-established in preclinical rodent models. However, little is known about how antecedent behavioral characteristics, such as valuation of hedonic reinforcers prior to drug use, influence fentanyl intake trajectories. Moreover, it is unclear if distinct escalation phenotypes are driven by genetic markers predictive of OUD susceptibility. Methods: Male and female Sprague-Dawley rats (n=72) were trained in a sucrose reinforcement task using a progressive ratio schedule. Individual differences in responsivity to sucrose were hypothesized to predict escalation of fentanyl intake. Rats underwent daily 1-h acquisition sessions for i.v. fentanyl self-administration (2.5 µg/kg; FR1) for 7 days, followed by 21 6-h escalation sessions, then tissue from prefrontal cortex was collected for RNA sequencing and qPCR. Latent growth curve and group-based trajectory modeling were used, respectively, to evaluate the association between sucrose reinforcement and fentanyl self-administration and to identify whether distinct escalation phenotypes can be linked to gene expression patterns. Results: Sucrose breakpoints did not predict fentanyl acquisition nor change during escalation, but did predict fentanyl intake on the first day of extended access. Permutation analyses found no associations between behavior and single gene expression, either overall or within our ascertained phenotypes. However, weighted genome correlation network analysis (WGCNA) and gene set enrichment analysis (GSEA) determined several gene modules linked to escalated fentanyl intake, including genes coding for voltage-gated potassium channels, calcium channels, and excitatory synaptic signaling. Transcription factor analyses identified EZH2 and JARID2 as potential transcriptional regulators associated with escalated fentanyl intake. Further, genome-wide association study (GWAS) term categories positively associated with terms relating to substance use disorders. Discussion: Escalation of opioid intake largely differs from motivation for natural rewards like sucrose. Further, the gene networks associated with fentanyl escalation suggest that engagement of select molecular pathways were associated with “addiction prone” behavioral endophenotypes, potentially representing druggable targets for OUD. Our extended in silico identification of SNPs and transcription factors associated with the “addiction prone” high escalating rats highlights the importance of integrating findings from translational preclinical models, supporting patient-centered treatment options for OUD.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE311548 | GEO | 2026/03/31

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The number of individuals diagnosed with opioid use disorder (OUD) has risen steeply because of the increased prescribing of opioid drugs like oxycodone for chronic pain relief. OUD is characterized by loss of control of drug taking, continued drug use in the presence of adverse consequences, and repeated relapses to drug taking. Repeated exposure to oxycodone self-administration can lead to addiction in certain rats while others remain unaffected. Understanding the molecular mechanisms between these two groups holds promise for developing strategies to combat addiction. To identify signaling pathways associated with oxycodone addition, this study used male Sprague-Dawley rats to self-administer oxycodone for 20 days according to short-(ShA, 3 h) and long-access (LgA, 9 h) paradigms. Animals were euthanized after 2 hours of self-administration cessation and their dorsal striata were used for RNA sequencing analysis. LgA rats escalated their oxycodone intake and developed into 2 phenotypes, named long-access high (LgA-H, addicted) and long-access lower (LgA-L, non-addicted) rats, based on the level of escalation and drug taken during the self-administration experiment. RNA sequencing revealed many differentially expressed genes in the oxycodone-addicted rats in comparison to other groups. DAVID analysis indicated that some of these genes were involved in potassium transport, ATP binding, and regulation of synaptic processes. Ingenuity pathway analysis (IPA) revealed previous involvement of some genes in OUD and cognitive processes. RNA sequencing and RT-PCR analysis of dorsal striatum samples unveiled a significant upregulation of potassium channel genes Kcnma1, Kcnk9, Kcnq1, Kcnd3, and Kcng3 in LgA-H rats, which was corelated with oxycodone intake. We also identified increased expression for Cldn3, Serping1, and Serpinh1 in ShA rats. Taken together, these observations identified potassium channels as potential targets for the treatment of oxycodone use disorder.

Project description:By using high-density oligonucleotide arrays, we profiled gene expression in reward-related brain regions of rats that developed escalated cocaine intake after extended access to cocaine (6 h per day). Rats allowed restricted daily access to cocaine (only 1 h) that displayed a stable level of cocaine intake and cocaine naive rats were used for controls. Four analysis methods were compared: Affymetrix microarray suite 4 and microarray suite 5, which use perfect-match-minus-mismatch models, and dchip and rma, which use perfect-match-only models to generate expression values. Results were validated by RT-PCR in individual animals from an independent replication of the experiment. A small number of genes was associated with escalated cocaine intake (ESC genes). Unexpectedly, of the brain regions examined [prefrontal cortex, nucleus accumbens, septum, lateral hypothalamus (LH), amygdala, and ventral tegmental area], the LH was the most transcriptionally responsive in escalation of cocaine intake. Most of the ESC genes identified are also expressed during synaptogenesis and synaptic plasticity and include genes that code for several presynaptic and postsynaptic proteins involved in neurotransmission. These results suggest that LH intrinsic circuitry undergoes a structural reorganization during escalation of cocaine use. This remodeling of LH circuitry could contribute to the chronic deficit in reward function that has been hypothesized to drive the transition to drug addiction. Results also support the value of using multiple analysis strategies to identify the most robust changes in gene expression and to compensate for the biases that affect each strategy. Experiment Overall Design: The experimental design for this study comprised three groups of rats (n = 8) with different daily access to a continuous schedule of i.v. cocaine self-administration (0.25 mg per injection): 0 h access per day (drug-naive control rats), 1 h access per day (ShA rats), or 6 h access per day (LgA rats). Experiment Overall Design: Gene expression profiling was then performed for each dissected brain region by using Affymetrix rat neurobiology arrays.

Dataset Information

Behavioral and transcriptomic markers of susceptibility to escalate fentanyl intake.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets