Remifentanil self-administration in mice promotes sex-specific prefrontal cortex dysfunction underlying deficits in cognitive flexibility

Anderson, Erik; Engelhardt, Annabel; Demis, Skyler; Porath, Elissa; Hearing, Matthew

doi:10.1038/s41386-021-01028-z

Cited by 31 publications

(26 citation statements)

References 72 publications

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“…In our study, female mice reliably consume more fentanyl than male mice, even when provided free choice throughout. This finding aligns well with recent work showing female mice are resistant to devaluation of oral fentanyl ( Monroe and Radke, 2021 ), self-administer more oral oxycodone ( Phillips et al, 2020 ), intravenous heroin ( Towers et al, 2019 ), and remifentanil ( Anderson et al, 2021 ). Further work is needed to establish if stress exacerbates the sex-differences in operant opioid self-administration.…”

Section: Discussionsupporting

confidence: 91%

Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice

Franco

Wulff

Lobo

et al. 2022

Front. Behav. Neurosci.

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Chronic stress can increase the risk of developing a substance use disorder in vulnerable individuals. Numerous models have been developed to probe the underlying neurobiological mechanisms, however, most prior work has been restricted to male rodents, conducted only in rats, or introduces physical injury that can complicate opioid studies. Here we sought to establish how chronic psychosocial stress influences fentanyl consumption in male and female C57BL/6 mice. We used chronic social defeat stress (CSDS), or the modified vicarious chronic witness defeat stress (CWDS), and used social interaction to stratify mice as stress-susceptible or resilient. We then subjected mice to a 15 days fentanyl drinking paradigm in the home cage that consisted of alternating forced and choice periods with increasing fentanyl concentrations. Male mice susceptible to either CWDS or CSDS consumed more fentanyl relative to unstressed mice. CWDS-susceptible female mice did not differ from unstressed mice during the forced periods, but showed increased preference for fentanyl over time. We also found decreased expression of nucleus accumbens Rho GTPases in male, but not female mice following stress and fentanyl drinking. We also compare fentanyl drinking behavior in mice that had free access to plain water throughout. Our results indicate that stress-sensitized fentanyl consumption is dependent on both sex and behavioral outcomes to stress.

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Section: Discussionsupporting

confidence: 91%

Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice

Franco

Wulff

Lobo

et al. 2022

Front. Behav. Neurosci.

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“…food choice procedure, male rats are more sensitive to fentanyl than females [ 37 ]. Remifentanil self-administration-induced neuroadaptations have been shown to differ between males and females, indicating that sex-specific interventions that target opioid-induced adaptations should be developed [ 38 ]. Species differences have been found in the expression of fentanyl withdrawal-associated pain.…”

Section: Influential Factorsmentioning

confidence: 99%

“…Chronic drug use is often accompanied by the loss of cognitive control, which is closely linked to the dysfunction of frontal cortex regions. Remifentanil self-administration causes a long-lasting hypoactive basal state of pyramidal neurons in the prelimbic cortex (PrL) in females, and this is driven by a reduction of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated excitatory synaptic transmission [ 38 ]. In addition, remifentanil self-administration has bidirectional effects on PrL layer 5/6 pyramidal neuron GABA B –G protein-coupled inwardly rectifying K + channel signaling in males [ 38 ].…”

Section: Reward and Stress Circuitsmentioning

confidence: 99%

“…Remifentanil self-administration causes a long-lasting hypoactive basal state of pyramidal neurons in the prelimbic cortex (PrL) in females, and this is driven by a reduction of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated excitatory synaptic transmission [ 38 ]. In addition, remifentanil self-administration has bidirectional effects on PrL layer 5/6 pyramidal neuron GABA B –G protein-coupled inwardly rectifying K + channel signaling in males [ 38 ]. Moreover, the chemogenetic activation of PrL pyramidal neurons reverses the deficits in cognitive flexibility, the basal hypoactive state, and remifentanil-induced plasticity [ 38 ].…”

Section: Reward and Stress Circuitsmentioning

confidence: 99%

“…In addition, remifentanil self-administration has bidirectional effects on PrL layer 5/6 pyramidal neuron GABA B –G protein-coupled inwardly rectifying K + channel signaling in males [ 38 ]. Moreover, the chemogenetic activation of PrL pyramidal neurons reverses the deficits in cognitive flexibility, the basal hypoactive state, and remifentanil-induced plasticity [ 38 ]. Reiner et al .…”

Section: Reward and Stress Circuitsmentioning

confidence: 99%

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Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse

et al. 2022

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Fentanyl is a fully synthetic opioid with analgesic and anesthetic properties. It has become a primary driver of the deadliest opioid crisis in the United States and elsewhere, consequently imposing devastating social, economic, and health burdens worldwide. However, the neural mechanisms that underlie the behavioral effects of fentanyl and its analogs are largely unknown, and approaches to prevent fentanyl abuse and fentanyl-related overdose deaths are scarce. This review presents the abuse potential and unique pharmacology of fentanyl and elucidates its potential mechanisms of action, including neural circuit dysfunction and neuroinflammation. We discuss recent progress in the development of pharmacological interventions, anti-fentanyl vaccines, anti-fentanyl/heroin conjugate vaccines, and monoclonal antibodies to attenuate fentanyl-seeking and prevent fentanyl-induced respiratory depression. However, translational studies and clinical trials are still lacking. Considering the present opioid crisis, the development of effective pharmacological and immunological strategies to prevent fentanyl abuse and overdose are urgently needed.

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Early social isolation stress increases addiction vulnerability to heroin and alters c-Fos expression in the mesocorticolimbic system

et al. 2022

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Remifentanil self-administration in mice promotes sex-specific prefrontal cortex dysfunction underlying deficits in cognitive flexibility

Cited by 31 publications

References 72 publications

Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice

Chronic Physical and Vicarious Psychosocial Stress Alter Fentanyl Consumption and Nucleus Accumbens Rho GTPases in Male and Female C57BL/6 Mice

Unique Pharmacology, Brain Dysfunction, and Therapeutic Advancements for Fentanyl Misuse and Abuse

Early social isolation stress increases addiction vulnerability to heroin and alters c-Fos expression in the mesocorticolimbic system

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