Sex differences in oral oxycodone self‐administration and stress‐primed reinstatement in rats

Fulenwider, Hannah D.; Nennig, Sadie E.; Hafeez, Hiba; Price, Michaela E.; Baruffaldi, Federico; Pravetoni, Marco; Cheng, Kejun; Rice, Kenner C.; Manvich, Daniel F.; Schank, Jesse R.

doi:10.1111/adb.12822

Cited by 45 publications

(49 citation statements)

References 55 publications

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“…Under fixed‐ratio schedules, female rats respond more for opioids than males (Carroll, Campbell, & Heideman, 2001; Cicero, Aylward, & Meyer, 2003; Mavrikaki, Pravetoni, Page, Potter, & Chartoff, 2017). Studies using oral or vapor delivery of opioids have also observed greater consumption among female rodents (Klein, 2001; Fulenwider, Nennig, Hafeez, et al., 2019; Moussawi et al., 2020), though others have not observed a difference (Monroe & Radke, 2020). In addition, female rats and mice have been shown to maintain self‐administration at higher levels than males for drugs such as cocaine (Lynch & Carroll, 1999), methamphetamine (Roth & Carroll, 2004), and EtOH (Sneddon et al., 2020).…”

Section: Female Vulnerability In Drug Self‐administration Studiesmentioning

confidence: 99%

Studying Sex Differences in Rodent Models of Addictive Behavior

2021

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Animal models of addictive behaviors are useful for uncovering neural mechanisms involved in the development of dependence and for identifying risk factors for drug abuse. One such risk factor is biological sex, which strongly moderates drug self‐administration behavior in rodents. Female rodents are more likely to acquire drug self‐administration behaviors, consume higher amounts of drug, and reinstate drug‐seeking behavior more readily. Despite this female vulnerability, preclinical addiction research has largely been done in male animals. The study of sex differences in rodent models of addictive behavior is increasing, however, as more investigators are choosing to include both male and female animals in experiments. This commentary is meant to serve as an introductory guide for preclinical investigators new to the study of sex differences in addiction. We provide an overview of self‐administration models, a broad view of female versus male self‐administration behaviors, and suggestions for study design and implementation. Inclusion of female subjects in preclinical addiction research is timely, as problem drug and alcohol use in women is increasing. With proper attention, design, and analysis, the study of sex differences in addiction has the potential to uncover novel neural mechanisms and lead to greater translational success for addiction research. © 2021 Wiley Periodicals LLC

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Section: Female Vulnerability In Drug Self‐administration Studiesmentioning

confidence: 99%

Studying Sex Differences in Rodent Models of Addictive Behavior

2021

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“…In a study investigating non–addiction-related reinforcement processes, female mice were biased toward negative reinforcement relative to positive reinforcement, in which females responded more to avoid an aversive shock than to receive a sucrose reward and were more sensitive to punishment than males ( 70 ). Female rodents more rapidly acquired morphine and heroin self-administration ( 22 , 71 , 72 ), self-administered more intravenous heroin ( 22 ) and fentanyl vapor ( 23 ) in long-access self-administration sessions, consumed more oral oxycodone during self-administration ( 73 , 74 ), and had higher motivation for fentanyl ( 75 ) than males. However, females showed no difference from males in stress-induced ( 73 ) or cue-induced reinstatement for oral oxycodone ( 74 ).…”

Section: Cues Associated With Negative Reinforcement Learningmentioning

confidence: 99%

“…Female rodents more rapidly acquired morphine and heroin self-administration ( 22 , 71 , 72 ), self-administered more intravenous heroin ( 22 ) and fentanyl vapor ( 23 ) in long-access self-administration sessions, consumed more oral oxycodone during self-administration ( 73 , 74 ), and had higher motivation for fentanyl ( 75 ) than males. However, females showed no difference from males in stress-induced ( 73 ) or cue-induced reinstatement for oral oxycodone ( 74 ). Opioid-dependent female mice also exhibited similar somatic signs of naloxone-precipitated heroin withdrawal to dependent male mice ( 22 ).…”

Section: Cues Associated With Negative Reinforcement Learningmentioning

confidence: 99%

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

et al. 2021

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Opioid use disorder (OUD) is a debilitating disorder that affects millions of people. Neutral cues can acquire motivational properties when paired with the positive emotional effects of drug intoxication to stimulate relapse. However, much less research has been devoted to cues that become conditioned to the aversive effects of opioid withdrawal. We argue that environmental stimuli promote motivation for opioids when cues are paired with withdrawal (conditioned withdrawal) and generate opioid consumption to terminate conditioned withdrawal (conditioned negative reinforcement). We review evidence that cues associated with pain drive opioid consumption, as patients with chronic pain may misuse opioids to escape physical and emotional pain. We highlight sex differences in withdrawal-induced stress reactivity and withdrawal cue processing and discuss neurocircuitry that may underlie withdrawal cue processing in dependent individuals. These studies highlight the importance of studying cues associated with withdrawal in dependent individuals and point to areas for exploration in OUD research.

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“…In 2017 in the United States, more than 10 million people reported prescription opioid misuse [1]. Despite its importance, modeling prescription opioid abuse in rodents has been challenging [2–5]. Certain aspects unique to prescription opioid use, such as route of administration and pattern of intake, may contribute to abuse liability and propensity toward relapse.…”

Section: Introductionmentioning

confidence: 99%

“…Second, prescription opioids are most commonly self-administered in a familiar setting such as the home (see Caprioli et al (2007) for a review [22]). Yet, where oral self-administration has been reported [2–4], experimental paradigms have required self-administration to take place in a novel context (e.g., operant chamber) and under food restriction. Environmental context (i.e., setting of drug taking) plays an important role in both drug taking and reinstatement, a finding that has been well-documented in humans and recapitulated by animal models [22–27].…”

Section: Introductionmentioning

confidence: 99%

Modeling features of addiction with an oral oxycodone self-administration paradigm

Murphy

Chang

Pareta

et al. 2021

Preprint

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Prescription opioid use is an initiating factor driving the current opioid epidemic. There are several challenges with modeling prescription opioid addiction. First, prescription opioids such as oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl. This oral route of administration determines the pharmacokinetic profile, which is critical for establishing reliable drug-reinforcement associations in animals. Second, intravenous opioid self-administration is typically performed with intermittent drug self-administration sessions in a separate environment from the home cage. This does not recapitulate prescription opioid use, which is characterized by continuous drug access in the patients homes. To model features of prescription opioid use and the transition to abuse, we developed an oxycodone self-administration paradigm that is administered in the homecage. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and exhibit preference for oxycodone, escalation of intake, physical signs of dependence, reinstatement of seeking after withdrawal, and a subset of animals demonstrate drug taking that is resistant to negative consequences. This model is therefore translationally relevant and can be useful for studying the neurobiological substrates specifically relevant to prescription opioid abuse.

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Sex differences in oral oxycodone self‐administration and stress‐primed reinstatement in rats

Cited by 45 publications

References 55 publications

Studying Sex Differences in Rodent Models of Addictive Behavior

Studying Sex Differences in Rodent Models of Addictive Behavior

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

Modeling features of addiction with an oral oxycodone self-administration paradigm

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