Modulation of heroin intake by ovarian hormones in gonadectomized and intact female rats

Smith, Mark A.; Ethridge, Sarah B.; Pearson, Tallia; Zhang, Huailin; Marcus, Madison M.; Ballard, Shannon; Casimir, Alexander T; Potter, Kenzie M.; Schmidt, Karl T.; Sharp, Jessica L.; Robinson, Andrea M.

doi:10.1007/s00213-020-05743-1

Cited by 20 publications

(23 citation statements)

References 46 publications

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“…However, this discrepancy may be due in part to differences in the route of oxycodone administration, the sample sizes tested, and the regularity of the estrous cycle in experimental subjects, among other incongruent variables. Moreover, the differences in IV oxycodone reinforcement that we observed across the estrous cycle are in agreement with other studies demonstrating estrous cycle-dependent fluctuations in the reinforcing effects of remifentanil (Thorpe et al, 2020) and heroin (Lacy et al, 2016;Smith et al, 2021) in intact female rats, suggesting that this may be a phenomenon shared among many, or perhaps all, mu opioid receptor agonists with abuse liability. Proestrus/estrus was associated with a significant attenuation of responses emitted on both the active and inactive operandum during oxycodone self-administration, raising the possibility that nonspecific disruptions in behavioral output may have contributed to observed changes in responding rather than a selective modulation of oxycodone's efficacy as a behavioral reinforcer per se.…”

Section: Oxycodone-maintained Responding Varies Across the Estrous Cyclesupporting

confidence: 92%

“…Second, in the present study, levels of active and inactive lever responding during cue-induced reinstatement tests (in the absence of ongoing drug reinforcement) did not significantly differ between females in proestrus/estrus vs. metestrus/diestrus. Finally, operant responding that is reinforced by a nondrug reinforcer (sucrose pellets) under short-access fixed-ratio or progressiveratio schedules of reinforcement is not different during either proestrus or estrus as compared to metestrus/diestrus in rats (Hecht et al, 1999;Smith et al, 2021). In light of these findings, we interpret reduced output on the inactive lever when oxycodone is self-administered during proestrus/estrus not as an indication of generalized behavioral suppression, but rather as a consequence of the diminished reinforcing efficacy of oxycodone that manifests as attenuated .…”

Section: Oxycodone-maintained Responding Varies Across the Estrous Cyclementioning

confidence: 96%

“…Direct comparisons between these experiments are difficult due to parametric differences between them including but not limited to species, strains, schedules of reinforcement, session durations, oxycodone doses/concentrations, and housing/feeding conditions, each of which may have contributed variability to the experimental results. Further complicating this narrative is recent evidence that fluctuations in ovarian hormones across the estrous cycle modulate the reinforcing efficacy of heroin in female rats (Lacy et al, 2016;Smith et al, 2021;Smith et al, 2022) (but see Stewart et al, 1996;Roth et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats

Hinds

Wojtas

Gallagher

et al. 2023

Preprint

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The increasing misuse of both prescription and illicit opioids has culminated in a national healthcare crisis in the United States. Oxycodone is among the most widely prescribed and misused opioid pain relievers and has been associated with a high risk for transition to compulsive opioid use. Here, we sought to examine potential sex differences and estrous cycle-dependent effects on the reinforcing efficacy of oxycodone, as well as on stress-induced or cue-induced oxycodone-seeking behavior, using intravenous (IV) oxycodone self-administration and reinstatement procedures. In experiment 1, adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone according to a fixed-ratio 1 schedule of reinforcement in daily 2-hr sessions, and a dose-response function was subsequently determined (0.003-0.03 mg/kg/inf). In experiment 2, a separate group of adult male and female Long-Evans rats were trained to self-administer 0.03 mg/kg/inf oxycodone for 8 sessions, followed by 0.01 mg/kg/inf oxycodone for 10 sessions. Responding was then extinguished, followed by sequential footshock-induced and cue-induced reinstatement tests. In the dose-response experiment, oxycodone produced a typical inverted U-shape function with 0.01 mg/kg/inf representing the maximally effective dose in both sexes. No sex differences were detected in the reinforcing efficacy of oxycodone. In the second experiment, the reinforcing effects of 0.01-0.03 mg//kg/inf oxycodone were significantly attenuated in females during proestrus/estrus as compared to metestrus/diestrus phases of the estrous cycle. Neither males nor females displayed significant footshock-induced reinstatement of oxycodone seeking, but both sexes exhibited significant cue-induced reinstatement of oxycodone seeking at magnitudes that did not differ either by sex or by estrous cycle phase. These results confirm and extend previous work suggesting that sex does not robustly influence the primary reinforcing effects of oxycodone nor the reinstatement of oxycodone-seeking behavior. However, our findings reveal for the first time that the reinforcing efficacy of IV oxycodone varies across the estrous cycle in female rats.

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Section: Oxycodone-maintained Responding Varies Across the Estrous Cyclesupporting

confidence: 92%

Section: Oxycodone-maintained Responding Varies Across the Estrous Cyclementioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats

Hinds

Wojtas

Gallagher

et al. 2023

Preprint

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show abstract

“…This is also consistent with a large body of work with psychostimulants and alcohol indicating that estradiol enhances initial vulnerability to drug use as defined by faster rates of acquisition and greater percent group acquisition (for review, see [39]). However, it is possible that the effects of estradiol differ for rates of acquisition versus initial levels of use, considering that several studies have reported no differences between OVX+E and OVX+V females in initial levels of heroin self-administration under short-access conditions (2–3 h/day, fixed-ratio 1 schedule; [41, 42]), even when assessed across a broad range of doses (0.3–50 µg/kg/infusion). Notably, this provides additional evidence for estradiol accelerating transitions between the stages of addiction in females with OVX+E females transitioning faster from initial to regular (or stable) opioid use than OVX+V females, similar to the transition from regular to escalated/uncontrolled opioid use.…”

Section: Discussionmentioning

confidence: 99%

Estradiol Enhances the Development of Addiction-Like Features in a Female Rat Model of Opioid Use Disorder

2023

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Rationale: Women are more vulnerable than men in many aspects of opioid use disorder (OUD); a major theory of sex differences in substance use disorders is that these differences are due to ovarian hormones with estradiol enhancing vulnerability in females. However, most of this evidence is for psychostimulants and alcohol; evidence with opioids is sparse. Objective: The goal of this study was to determine the impact of estradiol on vulnerability in females in a rat model of OUD. Method: Following self-administration training, ovariectomized (OVX) females with (E) or without (V) estradiol replacement were given extended (24h/day), intermittent-access (2, 5 min trials/h) to fentanyl for 10 days. Then, the development of three key features of OUD were assessed, including physical dependence, defined by the magnitude and time-course of weight loss during withdrawal, an enhanced motivation for fentanyl, assessed using a progressive-ratio schedule, and relapse vulnerability, assessed using an extinction/cue-induced reinstatement procedure. These later two characteristics were examined following 14 days of withdrawal when the phenotypes are known to be highly expressed. Results: OVX+E females self-administered markedly higher levels of fentanyl under extended, intermittent-access conditions and showed a longer time-course of physical dependence, a greater increase in motivation for fentanyl, and an enhanced sensitivity to the reinstating effects of fentanyl-associated cues compared to OVX+V rats. Severe health complications were also observed in OVX+E, but not OVX+V females, during withdrawal. Conclusion: These results indicate that, as with findings with psychostimulants and alcohol, estradiol enhances vulnerability in females to developing opioid addiction-like features and serious opioid-related health complications.

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“…Careful monitoring of menstrual cycle stage and ovarian hormone status in nonhuman primates has been able to demonstrate that alcohol intake is modulated by fluctuating ovarian hormones across the menstrual cycle 80 . Previous work has shown that psychostimulant 32,81 and opioid 82 -related behaviors are modulated across the estrous cycle in rodents, however demonstrating estrous cycle modulation of alcohol drinking has proven to be challenging 9,52,[83][84][85] . Nonetheless, many studies report that ovariectomy reduces alcohol intake 9,86 and E2 can enhance drinking in ovariectomized 9,56 and intact animals 57 , suggesting a role for fluctuating E2 across the intact female rodent estrous cycle in alcohol drinking.…”

Section: Discussionmentioning

confidence: 99%

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

Zallar,

Rivera-Irizarry,

Hamor

et al. 2023

Preprint

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The overconsumption of alcohol contributes to a multitude of negative health outcomes, especially in women, who are more susceptible to its effects and more likely to develop alcohol dependence than men with the same early history of alcohol consumption. Binge alcohol drinking is prominent during reproductive years and correlated with high circulating estrogen in women, and rodent studies show that female rodents with intact ovaries consume more alcohol than males. However, the causal role of ovarian E2 in intact animals in alcohol drinking has not been established. Here, we show that intact female mice consume more alcohol and display reduced avoidance behavior when they have elevated levels of circulating E2 during proestrus compared to other estrous cycle stages in individual mice. We found that high ovarian E2 promotes alcohol drinking in females, but not anxiolysis, through rapid nongenomic E2 signaling at ERα in the bed nucleus of the stria terminalis (BNST). Acute administration of intra-BNST E2 in low ovarian E2 mice enhanced binge alcohol intake, while acute systemic inhibition of E2 synthesis and acute blockade of ERα signaling in the BNST reversed the pro-drinking effects of high ovarian E2 status. In contrast, acute E2 manipulations were unable to alter the effects of ovarian E2 status on avoidance behavior, suggesting genomic mechanisms are required for the anxiolytic effects of ovarian E2. We further show that corticotropin-releasing factor (CRF) neurons in the BNST are an important mediator of these effects of rapid E2 signaling, as high E2 rapidly enhanced synaptic excitation of BNSTCRFneurons and promoted their pro-alcohol drinking behavioral role. Thus, we uncover a mechanism by which ovarian hormones in intact female mice control alcohol drinking behavior, and we provide the first mechanism by which ovarian E2 control of behavior is mediated by a rapid, nongenomic signaling mechanism.

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Modulation of heroin intake by ovarian hormones in gonadectomized and intact female rats

Cited by 20 publications

References 46 publications

Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats

Effects of sex and estrous cycle on intravenous oxycodone self-administration and the reinstatement of oxycodone-seeking behavior in rats

Estradiol Enhances the Development of Addiction-Like Features in a Female Rat Model of Opioid Use Disorder

Rapid nongenomic estrogen signaling controls alcohol drinking behavior

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