Transcriptomics in the nucleus accumbens shell reveal sex- and reinforcer-specific signatures associated with morphine and sucrose craving

Mayberry, Hannah L.; Bavley, Charlotte C.; Karbalaei, Reza; Peterson, Drew R.; Bongiovanni, Angela R.; Ellis, Alexandra S.; Downey, Sara H.; Toussaint, Andre B.; Wimmer, Mathieu E.

doi:10.1038/s41386-022-01289-2

Cited by 17 publications

(11 citation statements)

References 101 publications

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“…On the other hand, E2F1 , E2F Transcription Factor 1, is part of a well-defined family of transcription factors involved in addiction-relevant behavior ( 33–35 ). Interestingly, E2F1 has been implicated in coordinating transcriptional responses to fentanyl abstinence ( 36 ) and abstinence from morphine self-administration ( 37 ) within the NAc. Thus, these genes and others identified represent strong candidates as causal players in transcriptional mechanisms driving of OUD vulnerability.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit

Browne

Futamura

Minier-Toribio

et al. 2023

Preprint

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Opioid use disorder (OUD) looms as one of the most severe medical crises currently facing society. More effective therapeutics for OUD requires in-depth understanding of molecular changes supporting drug-taking and relapse. Recent efforts have helped advance these aims, but studies have been limited in number and scope. Here, we develop a brain reward circuit-wide atlas of opioid-induced transcriptional regulation by combining RNA sequencing (RNAseq) and heroin self-administration in male mice modeling multiple OUD-relevant conditions: acute heroin exposure, chronic heroin intake, context-induced drug-seeking following prolonged abstinence, and heroin-primed drug-seeking (i.e., relapse). Bioinformatics analysis of this rich dataset identified numerous patterns of molecular changes, transcriptional regulation, brain-region-specific involvement in various aspects of OUD, and both region-specific and pan-circuit biological domains affected by heroin. Integrating RNAseq data with behavioral outcomes using factor analysis to generate an addiction index uncovered novel roles for particular brain regions in promoting addiction-relevant behavior, and implicated multi-regional changes in affected genes and biological processes. Comparisons with RNAseq and genome-wide association studies from humans with OUD reveal convergent molecular regulation that are implicated in drug-taking and relapse, and point to novel gene candidates with high therapeutic potential for OUD. These results outline broad molecular reprogramming that may directly promote the development and maintenance of OUD, and provide a foundational resource to the field for future research into OUD mechanisms and treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit

Browne

Futamura

Minier-Toribio

et al. 2023

Preprint

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“…The precise mechanisms responsible for the sex differences described here and in the literature are yet to be elucidated. However, sex-specific changes in gene expression ( George et al, 2021 ) and/or dopaminergic reactivity ( Mayberry et al, 2022 ) with opioid use have recently been reported. Sex hormones may also influence the effects of opioids as opioid receptor availability ( Smith et al, 2006 ) and methadone doses needed for women in OUD treatment ( Chiang et al, 2017 ) have been shown to vary with estrogen and estradiol levels, respectively.…”

Section: Discussionmentioning

confidence: 99%

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

et al. 2023

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Background: The Department of Health and Human Services reports that prescription pain reliever (e.g., oxycodone) misuse was initiated by 4,400 Americans each day in 2019. Amid the opioid crisis, effective strategies to prevent and treat prescription opioid use disorder (OUD) are pressing. In preclinical models, the orexin system is recruited by drugs of abuse, and blockade of orexin receptors (OX receptors) prevents drug-seeking behavior. The present study sought to determine whether repurposing suvorexant (SUV), a dual OX receptor antagonist marketed for the treatment of insomnia, can treat two features of prescription OUD: exaggerated consumption and relapse.Methods: Male and female Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i. v., 8 h/day) in the presence of a contextual/discriminative stimulus (SD) and the ability of SUV (0–20 mg/kg, p. o.) to decrease oxycodone self-administration was tested. After self-administration testing, the rats underwent extinction training, after which we tested the ability of SUV (0 and 20 mg/kg, p. o.) to prevent reinstatement of oxycodone seeking elicited by the SD.Results: The rats acquired oxycodone self-administration and intake was correlated with the signs of physical opioid withdrawal. Additionally, females self-administered approximately twice as much oxycodone as males. Although SUV had no overall effect on oxycodone self-administration, scrutiny of the 8-h time-course revealed that 20 mg/kg SUV decreased oxycodone self-administration during the first hour in males and females. The oxycodone SD elicited strong reinstatement of oxycodone-seeking behavior that was significantly more robust in females. Suvorexant blocked oxycodone seeking in males and reduced it in females.Conclusions: These results support the targeting of OX receptors for the treatment for prescription OUD and repurposing SUV as pharmacotherapy for OUD.

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“…Numerous studies have identified molecular changes in the NAc that arise during opioid abstinence, or as a consequence of opioid use (Cahill et al, 2018; Ferguson et al, 2013; Lefevre et al, 2020; Martin et al, 2019; Mayberry et al, 2022; Spijker et al, 2004; Sun et al, 2016; Townsend et al, 2021), including recent work in postmortem human brain (Seney et al, 2021). Some notable similarities arise between our findings, and those of recent publications: neuronal morphology related genes are downregulated across species and paradigm (Lefevre et al, 2020; Mayberry et al, 2022; Townsend et al, 2021). Like our work in abstinent mice, Mayberry et al found downregulated Green Module genes in the NAc of male morphine self-administering rats (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, E2f1 overexpression may protect against dendritic atrophy but potentially engages mechanisms of self-regulation to maintain homeostasis in D1-MSNs by dampening select E2f1 targets. Coincidentally, abstinence from morphine self-administration was recently shown to downregulate genes with E2f1 binding motifs (Mayberry et al, 2022), and may thus be a way to manipulate maladaptive gene expression for both natural and synthetic opioids.…”

Section: Discussionmentioning

confidence: 99%

“…The nucleus accumbens (NAc) is a key locus in brain reward-circuitry that undergoes distinct molecular, cellular, and structural changes during opioid abstinence. Opioid withdrawal reduces dopamine release in the NAc (Acquas et al, 1991; Fox et al, 2017; Pothos et al, 1991; Rossetti et al, 1992) and induces numerous transcriptional changes dependent on opioid, sex, and abstinence duration (Cahill et al, 2018; Ferguson et al, 2013; Hofford et al, 2021; Martin et al, 2019; Mayberry et al, 2022; Spijker et al, 2004; Sun et al, 2016; Townsend et al, 2021). Opioid cessation also causes morphological and electrophysiological changes to NAc neurons.…”

Section: Introductionmentioning

confidence: 99%

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Negative emotional behavior during fentanyl abstinence is mediated by adaptations in nucleus accumbens neuron subtypes

Fox

Wulff

Franco

et al. 2022

Preprint

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SummaryOpioid discontinuation generates a withdrawal syndrome marked by a negative emotional state. Increased anxiety and dysphoria during opioid discontinuation are a significant barrier to achieving long-term abstinence in opioid-dependent individuals. Adaptations in brain-reward circuitry are implicated in the opioid abstinence syndrome, but current knowledge is limited to changes following natural and semi-synthetic opioids. Here we report abstinence from the synthetic opioid fentanyl engenders structural, functional, and molecular plasticity in nucleus accumbens neuron subtypes (MSNs) that mediate negative emotional behaviors. We show fentanyl abstinence causes dendritic atrophy and increased excitatory drive exclusive to D1-receptor containing MSNs. Using subtype specific RNAseq and Weighted Gene Co-Expression Network Analysis, we identified molecular signatures of fentanyl abstinence in MSN subtypes. We found a network of co-expressed genes downregulated selectively in D1-MSNs, and transcriptionally co-regulated by E2F1. We show targeting abstinence-induced molecular changes protects D1-MSNs from maladaptive plasticity and alleviates negative emotional behaviors after fentanyl abstinence.

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Transcriptomics in the nucleus accumbens shell reveal sex- and reinforcer-specific signatures associated with morphine and sucrose craving

Cited by 17 publications

References 101 publications

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit

Transcriptional signatures of heroin intake and seeking throughout the brain reward circuit

Suvorexant, an FDA-approved dual orexin receptor antagonist, reduces oxycodone self-administration and conditioned reinstatement in male and female rats

Negative emotional behavior during fentanyl abstinence is mediated by adaptations in nucleus accumbens neuron subtypes

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