The effects of chronic estradiol treatment on opioid self-administration in intact female rats

Sharp, Jessica L.; Ethridge, Sarah B.; Ballard, Shannon; Potter, Kenzie M.; Schmidt, Karl T.; Smith, Mark A.

doi:10.1016/j.drugalcdep.2021.108816

Cited by 14 publications

(7 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, heroin self-administration in female rats is highest during the nonproestrus phases of the ovarian cycle (Lacy et al, 2016; Schmidt et al, 2021), when levels of both estrogen and progesterone are relatively low. Conversely, heroin and remifentanil self-administration is reduced by administration of estrogen, but not by progesterone, indicating the estrogen receptor is critically involved (Sharp et al, 2021; Smith et al, 2020); however, also see (Roth et al, 2002). Thus, to the extent that PT150 may inhibit estrogen receptor function in females, it may explain the PT150-induced increase in fentanyl intake in females in the present study.…”

Section: Discussionmentioning

confidence: 99%

Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress.

Bardo¹,

Chandler²,

Denehy³

et al. 2023

Experimental and Clinical Psychopharmacology

View full text Add to dashboard Cite

There is comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD), perhaps because PTSD-like stressful experiences early in life alter the hypothalamic-pituitary-adrenal stress axis to increase the risk for OUD. The present study determined if the glucocorticoid receptor antagonist PT150 reduces the escalation of fentanyl intake in rats exposed to a "two-hit" model of early-life stress (isolation rearing and acute stress). Male and female rats were raised during adolescence in either isolated or social housing and then were given either a single acute stress (restraint and cold-water swim) or control treatment in young adulthood. Rats were then treated daily with PT150 (50 mg/kg, oral) or placebo and were tested for acquisition of fentanyl self-administration in 1-hr sessions, followed by escalation across 6-hr sessions. Regardless of PT150 treatment or sex, acquisition of fentanyl self-administration in 1-hr sessions was greater in isolate-housed rats compared to social-housed rats; the acute stress manipulation did not have an effect on self-administration even though it transiently increased plasma corticosterone levels. During the 6-hr sessions, escalation of fentanyl was observed across all treatment groups; however, there was a significant PT150 Treatment × Sex interaction. While males self-administered more than females overall, PT150 decreased intake in males and increased intake in females, thus negating the sex difference. Although PT150 may serve as an effective treatment for reducing the risk of OUD following early-life stress in males, further work is needed to determine the mechanism underlying the differential effects of PT150 in males and females. Public Health SignificanceThe effect of the glucocorticoid receptor antagonist PT150 on fentanyl self-administration in male and female rats subjected to early-life stress was examined. Males self-administered more than females, but PT150 eliminated this sex difference, with intake decreasing in males and increasing in females. PT150 may be useful to treat opioid use disorder in males, but not in females.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress.

Bardo¹,

Chandler²,

Denehy³

et al. 2023

Experimental and Clinical Psychopharmacology

View full text Add to dashboard Cite

show abstract

“…It is also possible that circulating gonadal hormones could account for sex differences in low/no shock FR1 responding for remifentanil. Indeed, estrous phase influences acquisition and FR1 responding for remifentanil self-administration and exogenous estradiol can modulate this self-administration (Lacy et al, 2020; Sharp et al, 2021; Thorpe et al, 2020). Given these effects of estrous cycle and gonadal hormones, a limitation of this study is that we did not account for these hormonal factors.…”

Section: Discussionmentioning

confidence: 99%

Biological sex influences the contribution of sign-tracking and anxiety-like behavior toward remifentanil self-administration.

Zumbusch¹,

Samson²,

Chernoff³

et al. 2023

Behavioral Neuroscience

View full text Add to dashboard Cite

Most people sample addictive drugs, but use becomes disordered in only a small minority. Two important factors that influence susceptibility to addiction are individual differences in personality traits and biological sex. The influence of traits on addiction-like behavior is well-characterized in preclinical models of cocaine selfadministration, but less is understood in regards to opioids. How biological sex influences trait susceptibility to opioid self-administration is likewise less studied than psychostimulants. Thus, we sought to elucidate how biological sex and several addiction-relevant traits interact with the propensity to self-administer the opioid remifentanil. We first screened female (n = 19) and male (n = 19) rats for four addiction-relevant traits: impulsivity, novelty place-preference, anxiety-like behavior, and attribution of incentive value to reward cues. Rats were then trained to self-administer remifentanil in a "conflict model" of drug self-administration. Rats had to endure an electric shock to access the response manipulandum that triggered an intravenous infusion of remifentanil. In male rats, high anxiety-like behavior was positively correlated with the number of drug infusions if the shock level was low or completely absent. In females, sign-tracking was predictive of greater resistance to punishment during drug seeking; an effect that was mediated by anxiety-like behavior. Females consumed more remifentanil under all conditions, and their drug seeking persisted in the face of significantly greater current than males. These findings demonstrate that the influence of behavioral traits over the propensity to self-administer opioids is dependent upon biological sex.

show abstract

“…In rodent studies, chronic estradiol treatment leads to quicker acquisition of cocaine, nicotine, and methamphetamine self-administration than in estradiol-depleted females ( Jackson et al, 2006 ; Larson et al, 2007 ; Kucerova et al, 2009 ; Flores et al, 2016 ). These effects, however, are dose and drug dependent, as increasing estradiol doses can reduce cocaine intake ( Hu and Becker, 2008 ), and estradiol-depleted rats exhibit higher opiate self-administration than those treated with estradiol ( Sharp et al, 2021 ). During habit formation, behavior changes from goal-directed to goal-independent (habitual) as control over drug intake switches from the DMS to the dorsolateral striatum (DLS; Corbit et al, 2012 ; Malvaez, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Estradiol Receptors Inhibit Long-Term Potentiation in the Dorsomedial Striatum

Lewitus,

Blackwell

2023

eNeuro

View full text Add to dashboard Cite

Estradiol, a female sex hormone and the predominant form of estrogen, has diverse effects throughout the brain including in learning and memory. Estradiol modulates several types of learning that depend on the dorsomedial striatum (DMS), a subregion of the basal ganglia involved in goal-directed learning, cued action-selection, and motor skills. A cellular basis of learning is synaptic plasticity, and the presence of extranuclear estradiol receptors ERα, ERβ, and G protein-coupled estrogen receptor (GPER) throughout the DMS suggests that estradiol may influence rapid cellular actions including those involved in plasticity. To test whether estradiol affects synaptic plasticity in the DMS, corticostriatal long-term potentiation (LTP) was induced using theta-burst stimulation inex vivobrain slices from intact male and female C57BL/6 mice. Extracellular field recordings showed that female mice in the diestrus stage of the estrous cycle exhibited LTP similar to male mice, while female mice in estrus did not exhibit LTP. Furthermore, antagonists of ERα or GPER rescued LTP in estrus females and agonists of ERα or GPER reduced LTP in diestrus females. In males, activating ERα but not GPER reduced LTP. These results uncover an inhibitory action of estradiol receptors on cellular learning in the DMS and suggest a cellular mechanism underlying the impairment in certain types of DMS-based learning observed in the presence of high estradiol. Due to the dorsal striatum’s role in drug addiction, these findings may provide a mechanism underlying an estradiol-mediated progression from goal-directed to habitual drug use.Significance StatementThis study examined the role of the female reproductive cycle and female sex hormones in synaptic plasticity, a cellular process that underlies learning behavior, in a brain region involved in goal-directed learning. Synaptic plasticity was similar between male mice and female mice in the low estradiol phase of the cycle. In contrast, female mice in a high estradiol phase of the cycle did not exhibit synaptic plasticity. The effect of estradiol was mediated by two of the three estradiol receptors found in the brain. The results have implications for the role of the female reproductive cycle in the development of drug addiction, which involves a progression from goal-directed learning to habit-based learning as drug use switches from recreational to compulsive.

show abstract

The effects of chronic estradiol treatment on opioid self-administration in intact female rats

Cited by 14 publications

References 41 publications

Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress.

Effect of the glucocorticoid receptor antagonist PT150 on acquisition and escalation of fentanyl self-administration following early-life stress.

Biological sex influences the contribution of sign-tracking and anxiety-like behavior toward remifentanil self-administration.

Estradiol Receptors Inhibit Long-Term Potentiation in the Dorsomedial Striatum

Contact Info

Product

Resources

About