Escalation and reinstatement of fentanyl self-administration in male and female rats

Malone, Samantha G.; Keller, Peggy S.; Hammerslag, Lindsey R.; Bardo, Michael T.

doi:10.1007/s00213-021-05850-7

Cited by 31 publications

(21 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The effects of vapor fentanyl self-administration on seeking behavior showed increased opioid motivation in females undergoing effort escalation. This is in line with research in naïve rats showing females acquire fentanyl self-administration more rapidly than males [45]. It is possible females are more sensitive to the rewarding effects of opioids, which may in turn lead to the higher opioid abuse rates in women [46].…”

Section: Discussionsupporting

confidence: 86%

Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain

Cermak

Centeno

Jabakhanji

et al. 2022

Preprint

View full text Add to dashboard Cite

We studied the behavioral consequences of fentanyl vapor self-administration (SA) in mice with and without chronic neuropathic pain (one month after spared-nerve injury(SNI) model or sham injury). We assessed fentanyl consumption, motivation, and seeking during as well as anxiety, hyperactivity, immobility, and pain for two regimens of fentanyl SA: 1) Dose escalation, where over a 3-week period mice are exposed (daily 2-hour sessions) to escalating numbers of fentanyl puffs per active nosepoke (from 1 puff/active nosepoke for first 3 days, up to 6 puffs/active nosepoke in days 16-18). 2) Effort escalation, where over a 3-week period (daily 2-hour sessions) mice need to increase effort to acquire the same amount of fentanyl (fixed ratio 1 (FR) = 1 active nosepoke results in 1 fentanyl puff, while second and third week we use FR5 and FR10). We observe sex-, injury- and regimen- dependent differences in outcomes. Importantly the dose escalation regimen resulted in higher seeking behavior (post forced abstinence, context and cue driven nosepoking in the absence of fentanyl delivery), long lasting increased anxiety, immobility, and hyperactivity, as well as transient but full pain relief in SNI mice. Therefore, this regimen seems a better rodent model for translating outcomes to human chronic pain patients managed with opioids.

show abstract

Section: Discussionsupporting

confidence: 86%

Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain

Cermak

Centeno

Jabakhanji

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Following recovery from surgery, rats were randomly assigned to self-administer one of four fentanyl doses (µg/kg/infusion): 0.25 (9 females and 8 males), 0.75 (9 females and 8 males), 1.5 (8 females and 8 males), or 3.0 (7 females and 8 males). These doses were selected because the majority of studies using fentanyl self-administration procedures in rodents use a dose of fentanyl ranging from 0.25 to 2.5 ug/kg ( Morgan et al, 2002 ; Wade et al, 2015 ; Bakhti-Suroosh et al, 2021 ; Dao et al, 2021 ; Fragale et al, 2021 ; Hammerslag et al, 2021 ; Malone et al, 2021 ; Martin et al, 2021 ); therefore, we selected a dose range that included both low (0.25 and 0.75 µg/kg/infusion) and moderate-to-high doses (1.5 and 3.0 µg/kg/infusion; Morgan et al, 2002 ; Wade et al, 2015 ; Martin et al, 2021 ; Dao et al, 2021 ; Malone et al, 2021 ; Hammerslag et al, 2021 ) in order to maximize the likelihood of sex and group differences in levels and patterns of fentanyl self-administration and subsequent effects on relapse vulnerability. Rats were trained to self-administer their assigned dose of fentanyl under a fixed-ratio 1 schedule with a 1-s time out following each infusion and a maximum of 40 infusions/day ( Bakhti-Suroosh et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Sex- and Dose-Dependent Differences in the Development of an Addiction-Like Phenotype Following Extended-Access Fentanyl Self-Administration

2022

View full text Add to dashboard Cite

Opioid use disorder (OUD) is a major epidemic in the United States, and fentanyl is a major culprit. The National Institute on Drug Abuse has highlighted an urgent need for research on the risks and outcomes of OUD with fentanyl; a better understanding of sex/gender differences is also critically needed given that the opioid epidemic has been particularly impactful on women. In response to this need, we developed a rat model of OUD with fentanyl and showed that sex impacts relapse vulnerability following extended-access self-administration under a low fentanyl dose. Here, our goal was to determine sex differences across a broad dose range, including high doses expected to maximize the expression of addiction-like features (e.g., vulnerability to relapse and physical dependence). Male and female rats were assigned to self-administer one of four fentanyl doses (0.25, 0.75, 1.5, and 3.0 µg/kg/infusion), and once they acquired, they were given extended (24-h/day), intermittent access (2, 5 min trials/h, fixed-ratio 1) to fentanyl for 10 days. Physical dependence (spontaneous weight loss) was assessed during early withdrawal, and relapse vulnerability was assessed on withdrawal day 15 using an extinction/cue-induced reinstatement procedure. Despite markedly higher intake in the high- versus low-dose groups, each group responded similarly during relapse testing (extinction and cue-induced reinstatement). However, number of infusions, or frequency of use, during extended access was predictive of later vulnerability to relapse, whereas total intake impacted physical dependence given that weight loss only occurred following the discontinuation of fentanyl self-administration at the three highest doses. Females self-administered more fentanyl each day and within each binge (active trial), and had longer lasting weight loss during withdrawal than males. Relapse vulnerability was also higher in females than males and highest in females tested during estrus. These findings indicate that sex is an important risk factor for patterns and levels of fentanyl intake, relapse, and physical dependence, and while fentanyl intake predicts physical dependence, frequency of use predicts relapse.

show abstract

“…This is critical from a translational perspective given that other studies examining sex differences in opioid self-administration show inconsistent results. In this regard, most studies report higher rates of opioid self-administration in females compared to males [88][89][90][91][92][93][94][95][96][97][98][99][100] while others fail to capture any sex differences [99][100][101][102] . Notably, one study found that males self-administer more oxycodone when demand is low (FR1) and this modest effect was on the number of infusions obtain rather than lever responses, suggesting that males were only slightly more efficient during the 6-s timeout periods 103 .…”

Section: Discussionmentioning

confidence: 99%

Time-dependent enhancement in ventral tegmental area dopamine neuron activity drives pain-facilitated fentanyl intake in males

Higginbotham

Abt

Teich

et al. 2022

Preprint

View full text Add to dashboard Cite

Pain affects over 50% of US adults. Opioids are potent analgesics used to treat pain symptoms but are highly prone to abuse, creating a major dilemma for public health. Evidence suggests that the proclivity for opioid abuse under pain conditions varies between sexes. However, the neural mechanisms underlying sex-specific effects of pain on opioid use are largely unclear. Here, we recapitulate clinical findings and demonstrate that pain increases self-administration of the widely abused opioid, fentanyl, selectively in male rats. These behavioral effects develop over time and are paralleled by sex- and pain-specific effects on fentanyl-evoked ventral tegmental area (VTA) dopamine (DA) neuron activity, a critical mediator of motivation and reward. Using in vivo fiber photometry, we show that tonic VTA DA neuron activity is attenuated in males with pain. In contrast, phasic VTA DA neuron responses to self-administered fentanyl increase in magnitude at later timepoints and correspond with increases in fentanyl intake. The protracted increase in fentanyl-evoked VTA DA activity is necessary for pain to enhance fentanyl self-administration in males because chemogenetic inhibition of VTA DA neurons normalized fentanyl intake and associated fentanyl-evoked VTA DA neuron responses. These findings reveal time-dependent and sex-specific pain-induced adaptations to VTA DA neuron function that underlie maladaptive patterns of opioid use.

show abstract

Escalation and reinstatement of fentanyl self-administration in male and female rats

Cited by 31 publications

References 57 publications

Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain

Pattern of Self-Administered Vapor Fentanyl Exposure Determines Long-term Behavior Consequences, in Mice with or without Neuropathic Pain

Sex- and Dose-Dependent Differences in the Development of an Addiction-Like Phenotype Following Extended-Access Fentanyl Self-Administration

Time-dependent enhancement in ventral tegmental area dopamine neuron activity drives pain-facilitated fentanyl intake in males

Contact Info

Product

Resources

About