Sex differences in effects of predictable and unpredictable footshock on fentanyl self-administration in rats.

Lc, Klein; Ej, Popke; Ne, Grunberg

doi:10.1037//1064-1297.5.2.99

Cited by 33 publications

(6 citation statements)

References 5 publications

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“…We observed significant sex differences in fentanyl consumption, with females consuming more fentanyl than males, particularly at the 30 µg/mL concentration, however, we have observed that female mice consume more liquid than male mice in general 49,50 . While studies investigating sex differences in oral fentanyl consumption are extremely limited, our work agrees with existing opioid self-administration literature that consistently shows increased opioid self-administration in females versus males 8,13,51–53 .…”

Section: Discussionsupporting

confidence: 89%

Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice

Downs,

Kmiec,

McElligott

2023

Preprint

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The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the illicit drug supply. While many previous studies on fentanyl and other opioids have focused on intravenous administration, other routes of administration remain relatively understudied. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed enough fentanyl to precipitate withdrawal with naloxone, with males having more severe withdrawal symptoms. Fentanyl consumption disrupted normal sleep rhythms in both male and female mice. We also performed behavioral assays to measure approach/avoidance behavior and reward-seeking during fentanyl abstinence. Female mice showed more avoidance behaviors in the open field assay, whereas male mice showed evidence of these behaviors in the light/dark box assay. Female mice also showed increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning. Our experiments show that long-term oral fentanyl consumption disrupts sleep rhythms, promotes anxiety-like behavior, increases motivation for reward, and disrupts fear extinction learning. This model could be useful to further study fentanyl withdrawal syndrome and anxiety-like phenotypes associated with protracted fentanyl withdrawal.

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Section: Discussionsupporting

confidence: 89%

Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice

Downs,

Kmiec,

McElligott

2023

Preprint

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“…Preclinical studies consistently report that females self-administer more heroin [ 9 , 107 – 109 ] and fentanyl [ 110 ] relative to males. Heroin self-administration varies across the estrous cycle, but it does so in a different manner than cocaine.…”

Section: Role Of Ovarian Hormones In Preclinical Models Of Opioid Use...mentioning

confidence: 99%

Estradiol and Mu opioid-mediated reward: The role of estrogen receptors in opioid use

Ethridge,

Smith

2023

Addiction Neuroscience

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“…Although only 30% of gastrointestinal tract–absorbed fentanyl escapes first-pass metabolism ( Darwish et al, 2007 ), oral fentanyl misuse can still induce increased blood fentanyl levels and cause death ( Woodall et al, 2008 ). Second, the oral fentanyl self-administration model has been widely used to establish stable fentanyl-maintained behavior in preclinical studies ( Shaham et al, 1993 ; Klein et al, 1997 ; Wade et al, 2008 ; Monroe and Radke, 2021 ). We also investigated the potential roles of IGF-1 in regulating fentanyl-seeking behavior and N-methyl-D-aspartate receptor (NMDAR)- and AMPAR-mediated excitatory synaptic transmission.…”

Section: Introductionmentioning

confidence: 99%

IGF-1 Microinjection in the Prefrontal Cortex Attenuates Fentanyl-Seeking Behavior in Mice

Yue

Wang

et al. 2023

International Journal of Neuropsychopharmacology

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Background Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder with an enormous socioeconomic burden. Opioid overdose deaths have reached an epidemic level, especially for fentanyl. One of the biggest challenges to treat OUD is the relapse to drug seeking after prolonged abstinence. Abnormalities in insulin-like growth factor-1 (IGF-1) have been reported in various neurological and psychiatric disorders, including OUD. However, whether IGF-1 and its downstream signaling pathways are associated with relapse to fentanyl seeking remains unclear. Methods Mice were subjected to daily 2-h fentanyl (10 μg/ml, 27μl/infusion) oral self-administration training for 14 days, followed by 14-day fentanyl cessation. Expression levels of IGF-1/IGF-1 receptor (IGF-1R) and downstream signaling pathways in the dorsomedial prefrontal cortex (dmPFC) were detected. Then, IGF-1 was bilaterally microinjected into the dmPFC from fentanyl cessation day 9 to day 13. Fentanyl-seeking behavior and excitatory synaptic transmission of pyramidal neurons in PFC were evaluated. Results We found that 14-daycessation from fentanyl oral self-administration caused significant downregulation of IGF-1 and IGF-1R phosphorylation in the dmPFC. These changes were accompanied by inhibition of downstream Aktand S6 signaling pathway. In addition, local administration of IGF-1 in the dmPFC attenuated context-induced fentanyl-seeking behavior. Furthermore, electrophysiology and immunohistochemistry analyses showed that IGF-1 blocked fentanyl-induced reduction of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors-mediated excitatory synaptic transmission as well as synaptic expression of AMPAR and NMDAR subunits. Conclusions These results suggest that IGF-1 in the PFC plays a pivotal role in regulating fentanyl seeking after prolonged cessation from fentanyl oral self-administration.

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Sex differences in effects of predictable and unpredictable footshock on fentanyl self-administration in rats.

Cited by 33 publications

References 5 publications

Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice

Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice

Estradiol and Mu opioid-mediated reward: The role of estrogen receptors in opioid use

IGF-1 Microinjection in the Prefrontal Cortex Attenuates Fentanyl-Seeking Behavior in Mice

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