Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

Bravo, Isabel M.; Luster, Brennon; Flanigan, Meghan E.; Perez, Patric J.; Cogan, Elizabeth S.; Schmidt, Karl T.; McElligott, Zoé A.

doi:10.1101/689521

Cited by 11 publications

(16 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found fentanyl exposed mice exhibited increased naloxone precipitated withdrawal signs, suggesting our method produces a degree of opioid dependence. Similar to other studies on protracted opioid abstinence (Bai et al, 2014; Becker et al, 2017; Bravo et al, 2020), we also found decreased social behavior and increased anxiety-like behavior in both sexes of abstinent mice. Since drug exposure canalter HPA axis function (Wemm and Sinha, 2019), we also assessed stress-susceptibility in male mice, using a subthreshold social stressor sometimes termed “microdefeat”(Golden et al, 2011).…”

Section: Discussionsupporting

confidence: 91%

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

Fox

Wulff

Franco

et al. 2022

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 91%

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

Fox

Wulff

Franco

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition, the symptom expression was positively associated with the number of heroin infusions the animal took at the beginning of the study. Studies in which animals received forced opioid injections have reported hormone abnormalities (Li et al, 2010), persistent anxiety (Bravo et al, 2019), sleep disturbance (Khazan & Colasanti, 1972), and increased motivation to seek heroin (Bossert et al, 2016; Shen et al, 2011) during the protracted period. These behaviors were not fully examined here and would be important next steps to be explored using this paradigm.…”

Section: Discussionmentioning

confidence: 99%

Establishing preclinical withdrawal syndrome symptomatology following heroin self-administration in male and female rats.

Gipson

Dunn

Bull

et al. 2021

Experimental and Clinical Psychopharmacology

View full text Add to dashboard Cite

Opioid use disorder (OUD) is a significant health problem, and understanding mechanisms of various aspects of OUD including drug use and withdrawal is important. Preclinical models provide an ideal opportunity to evaluate mechanisms underlying opioid withdrawal. Current models are limited by their reliance upon forced opioid administration, focus on the acute (and not protracted) syndrome, and exclusion of females. In this study, male and female rats selfadministered heroin (maintenance dose of 12.5 µg/kg/infusion) opioid withdrawal following abrupt discontinuation was measured. In Phase 1, acute withdrawal symptoms were rated in male and female rats at 0, 16, 48, and 72 hrs following the last self-administration session. Total somatic signs increased until 48 hrs (predominantly in females), and heroin intake positively correlated with total somatic signs at the 48 and 72 hr timepoints. Measures of hyperactivity and anxiety-like behavior increased by 16 and 48 hrs, respectively. In Phase 2, symptoms were assessed at baseline, acute, and protracted (168 and 312 hrs after self-administration) timepoints in a subset of male and female rats from Phase 1. The total number of somatic signs did not differ across timepoints, though females displayed significantly higher body temperature at all timepoints compared to males, indicating sex-specific protracted withdrawal symptomatology. These data provide a thorough characterization of rodent opioid withdrawal symptomatology following selfadministration and abrupt discontinuation that serve as a foundation for future studies designed to mimic the human experience, and demonstrate the importance of characterizing acute and protracted withdrawal with sex-specificity in preclinical models of opioid self-administration.

show abstract

“…We know little about how opioid withdrawal differentially affects the sexes in rodent models. However, we do know male and female mice experience withdrawal differently, evident in both their behavior responses and the neurobiology [5,27]. Opioid related sleep disturbances can worsen both pain and withdrawal symptoms.…”

Section: Introductionmentioning

confidence: 99%

Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice

Bedard

Lord

Perez

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

The opioid epidemic has increased dramatically over the last few decades resulting in many suffering from opioid use disorder (OUD). The prevalence of opioids and opioid overdose has been driven by the development of new synthetic opioids, increased availability of prescription opioids, and more recently, the COVID-19 pandemic. As we see increased in exposure to opioids, the United States has also seen increases in the frequency of instances of Narcan (naloxone) administration as a life saving measure for respiratory depression, and, thus, consequently, naloxone-precipitated withdrawal. Sleep dysregulation is one of the main symptoms of OUD and opioid withdrawal syndrome, and therefore should be a key facet of animal models of OUD. Here we examine the effect of precipitated and spontaneous morphine withdrawal on sleep behaviors in C57BL/6J. We find that morphine administration and withdrawal dysregulates sleep, however not equally across morphine exposure paradigms and not qualitatively the same across sexes. Furthermore, many environmental triggers promote relapse to drug seeking/taking behavior, and the stress of disrupted sleep may fall into that category. We find that sleep deprivation dysregulates sleep in mice that had previous opioid withdrawal experience. These data suggest that the 3-day precipitated withdrawal paradigm has the most profound effects on opioid induced sleep dysregulation, and that further validate the construct of the 3-day precipitated withdrawal model as a model for opioid dependence and OUD.

show abstract

Divergent behavioral responses in protracted opioid withdrawal in male and female C57BL/6J mice

Cited by 11 publications

References 39 publications

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

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

Establishing preclinical withdrawal syndrome symptomatology following heroin self-administration in male and female rats.

Probing different paradigms of morphine withdrawal on sleep behavior in male and female C57BL/6J mice

Contact Info

Product

Resources

About