Extended access to fentanyl vapor self-administration leads to addiction-like behaviors in mice: Blood chemokine/cytokine levels as potential biomarkers

Marchette, Renata C.N.; Carlson, Erika R.; Said, Nadia; Koob, George F.; Vendruscolo, Leandro F.

doi:10.1016/j.addicn.2022.100057

Cited by 8 publications

(5 citation statements)

References 77 publications

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“…The current study builds upon previous findings and demonstrates that 2 hours of access to 2.5 µg/kg/infusion of fentanyl over 14 days is sufficient to establish escalation of fentanyl intake and result in withdrawal symptoms in mice. Previous literature has investigated rodent models of opioid dependence, including morphine (47)(48)(49), oxycodone (10,12,50,51), heroin (6,(52)(53)(54), remifentanil (34,(55)(56)(57)(58), and fentanyl (24,33,36,38,(59)(60)(61)(62)(63)(64)(65)(66), using various routes of administration, with the majority of studies done in rats. IVSA of fentanyl has been widely studied in rats (24,25,(59)(60)(61)(62)(67)(68)(69)(70)(71), with findings demonstrating mixed results on the development of dependence and withdrawal signs.…”

Section: Discussionmentioning

confidence: 99%

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Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Chen,

Xiao,

Kimbrough

2024

Preprint

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BackgroundThe rise in overdose deaths from synthetic opioids, especially fentanyl, necessitates the development of preclinical models to study fentanyl use disorder (FUD). While there has been progress with rodent models, additional translationally relevant models are needed to examine excessive fentanyl intake and withdrawal symptoms.MethodsThe study performed intravenous self-administration (IVSA) of fentanyl in male and female C57BL/6J mice for 14 days. Mechanical pain sensitivity during withdrawal was assessed using the von Frey test. Anxiety-like behavior was evaluated via the open field test one-week into abstinence and incubation of craving for fentanyl was assessed four weeks into abstinence.ResultsBoth male and female mice demonstrated a significant escalation in fentanyl intake over the 14 days of self-administration, with significant front-loading observed in the final days of self-administration. Increased mechanical pain sensitivity was present from 36- to 48-hour into withdrawal and increased anxiety-like behavior was found 1 week into abstinence. Four weeks into abstinence, mice showed significantly higher active lever pressing than the final self-administration session prior to abstinence.ConclusionsThe study establishes a translationally relevant mouse model of IVSA of fentanyl, effectively encapsulating critical aspects of FUD, including escalation of drug intake, front-loading behavior, withdrawal symptoms, and prolonged craving for drug into abstinence. This model offers a robust basis for further exploration into behavioral and neurobiological mechanisms involved in fentanyl dependence and potential therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

“…Thus, it is critical to establish models of FUD in mice, including IVSA models. A previous study showed that mice are capable of initiating IVSA of fentanyl (33), and other mouse models have demonstrated withdrawal symptoms following oral or vapor self-administration (36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Chen,

Xiao,

Kimbrough

2024

Preprint

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“…Alcohol-dependent mice treated with anti-IL-17a antibodies reduced their voluntary alcohol intake 75 , suggesting that modulation of IL-17a may impact drug seeking behavior. Additionally, IL-17a is proinflammatory and was reported upregulated in the blood of mice following long-access exposure to fentanyl vapor 76 , as well as in the PFC after methamphetamine exposure 77 . Treatment with a purinergic P2X7 receptor antagonist, which blocks pro-inflammatory signaling 78 , inhibits methamphetamine-induced upregulation of IL-17a in the PFC, as well as methamphetamine- induced conditioned place preference 77 .…”

Section: Discussionmentioning

confidence: 99%

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats

Floris,

Dabrowski,

Zanda

et al. 2024

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Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT2AR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT2AR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naïve rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated ∼2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor,Il17ra. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, includingIl17a, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.

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“…Inhalation is a route of drug administration common to many that use opioid drugs nonmedically (Parent et al 2021). We and others have reported success in using Electronic Nicotine Delivery Systems (ENDS), or more generally termed Electronic Drug Delivery Systems (EDDS), to deliver behaviorally active doses of opioids by inhalation in preclinical rodent models (Gutierrez et al 2021; Gutierrez et al 2022b; Gutierrez et al 2020; Marchette et al 2023; McConnell et al 2021; Moussawi et al 2020; Vendruscolo et al 2018). EDDS technology has also been used to probe the lasting effects of repeated adolescent vapor inhalation of drugs such as nicotine (Gutierrez et al 2024; Gutierrez et al 2023), THC (Gutierrez et al 2024; Nguyen et al 2020), and heroin (Gutierrez et al 2022a), and to determine lasting effects of in utero exposure to THC (Breit et al 2022; Breit et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Persistent effects of repeated adolescent and adult heroin vapor inhalation in female Wistar rats

Gutierrez,

Taffe

2024

Preprint

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Adolescent drug exposure has been associated with more severe mental health outcomes related to substance abuse and anxiety disorders. The aim of the present study was to contrast the long-term effects of repeated heroin vapor inhalation during adolescence with similar heroin exposure in adulthood. Groups of female Wistar rats underwent twice daily 30-minute sessions of heroin or propylene glycol (control) vapor inhalation from postnatal days (PND) 36-45 or PND 85-94, respectively. Nociception was assessed after vapor inhalation sessions and forty days later, for the Adolescent-Exposed and Adult-Exposed groups. Anxiety-like behavior was assessed with an elevated plus-maze (EPM) and spatial learning was assessed with a Barnes maze. Acute effects of naloxone (0.3 mg/kg, i.p.) and heroin (0.5 and 1.0 mg/kg, s.c.) on thermal nociception were determined on PND 140/189 and PND 149/198, respectively. Repeated heroin vapor inhalation produced anti-nociceptive tolerance across sessions in both adolescent and adult rats, with the adolescents exhibiting more complete tolerance. Heroin vapor inhalation produced anxiolytic effects, regardless of age of exposure. There were no effects of heroin on spatial learning. Naloxone produced acute hyperalgesia in all but the Adolescent-Exposed heroin group, and heroin anti-nociception was blunted in both heroin-exposed groups at the highest heroin dose. Repeated heroin vapor inhalation can produce lasting effects on nociception and anxiety-like behavior that persist for months after the exposure. Importantly, these findings suggest that adolescent exposure to heroin vapor produces specific effects on nociception that are not observed when exposure occurs in adulthood.

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Extended access to fentanyl vapor self-administration leads to addiction-like behaviors in mice: Blood chemokine/cytokine levels as potential biomarkers

Cited by 8 publications

References 77 publications

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Escalation of intravenous fentanyl self-administration and assessment of withdrawal behavior in male and female mice

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats

Persistent effects of repeated adolescent and adult heroin vapor inhalation in female Wistar rats

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