Sex/Gender Differences in the Time-Course for the Development of Substance Use Disorder: A Focus on the Telescoping Effect

Towers, Eleanor Blair; Williams, Ivy L.; Qillawala, Emaan I.; Rissman, Emilie F.; Lynch, Wendy J.

doi:10.1124/pharmrev.121.000361

Cited by 46 publications

(25 citation statements)

References 403 publications

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“…The purpose of this study was to determine the impact of estradiol on fentanyl intake and the development of an opioid addiction-like phenotype in females. Similar to findings with psychostimulants and alcohol (for review, see [39]), we found that estradiol replacement in OVX females increased fentanyl use and the expression of several key features of an addiction-like phenotype. More specifically, compared to OVX+V, OVX+E females were more likely to acquire fentanyl self-administration rapidly and to escalate their fentanyl use over time under extended, IntA conditions, indicating that estradiol may accelerate transitions from initial to regular opioid use and from regular opioid use to escalated/dysregulated opioid use.…”

Section: Discussionsupporting

confidence: 87%

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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Section: Discussionsupporting

confidence: 87%

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

2023

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“…These data, along with the sex differences in bodyweight loss, suggest sexual dimorphism of the KD that need further exploration. No studies have investigated directly the influence of sexual dimorphisms of diet on OUD, but several have determined other factors driving OUD responses, such as exercise, weight gain, and also the development of OUD 34 – 36 .…”

Section: Discussionmentioning

confidence: 99%

Ketogenic diet enhances the effects of oxycodone in mice

Trinko

Diaz

Foscue

et al. 2023

Sci Rep

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Opioids have been used to manage pain for thousands of years, but they have significant potential for abuse. Prescription opioids, like oxycodone, are associated with 32% of overdoses, that have reached a total of 75,673 deaths in 2021. A major challenge is maximizing their therapeutic potential while minimizing the negative side effects including opioid use disorder (OUD). The Ketogenic Diet (KD) has been reported to reduce pain and decrease the severity of alcohol use disorder, yet its effects on oxycodone responses remain unknown. KD mice displayed increased oxycodone-induced locomotor activity and enhanced antinociceptive effects of oxycodone, suggesting a dietary effect on opiate sensitivity. Male KD mice exposed to chronic oxycodone exhibited increased naloxone-induced jumps, suggesting a sex-specific effect of diet on opioid withdrawal. Consistent with this, male KD mice self-administered less oxycodone while female KD mice did not differ from controls. Finally, no effect of KD on motivation to obtain oxycodone was observed during a progressive ratio schedule. These data suggest sex-biased effects of KD on responses to opioids that should be considered and potentially leveraged in both clinical pain management and treatment of OUD.

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“…Although extrapolation of animal data to humans requires caution, this study might offer insight into the biological sex differences observed in certain disorders. For instance, the initial delay in establishing contextual control observed here in females might contribute to the rapid progression of SUD or PTSD observed in women following initial drug use or trauma [13, 14, 70, 71]. Conversely, the more stable contextual control ultimately achieved by females after extended training observed here might contribute to the better prognosis for women following behavioral and cognitive treatments for these disorders [71–73], and might be due, in part, to increased OFC engagement [74].…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, the prevalence and symptomatology of these disorders vary between sexes. For example, the incidence of schizophrenia and autism is higher in men [12] while women are more at risk of developing SUD or PTSD following initial drug use or trauma [13, 14]. This disparity might be due, in part, to subtle sex differences in executive strategies [15–17].…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Discrimination Behavior and Orbitofrontal Engagement During Context-Gated Reward Prediction

Peterson,

Maheras,

Chavira

et al. 2023

Preprint

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Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism, PTSD, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two reward-predictive cues was informed by the presence, or absence, of a background contextual feature (A:X+ / X− / A:Y− / Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between speed and robustness in the acquisition of contextual modulation. The different distribution of sexes along the Fast↔Steady continuum might reflect different levels of engagement of the orbitofrontal cortex, and might have implications for our understanding of sex differences in psychiatric disorders.

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Sex/Gender Differences in the Time-Course for the Development of Substance Use Disorder: A Focus on the Telescoping Effect

Cited by 46 publications

References 403 publications

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

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

Ketogenic diet enhances the effects of oxycodone in mice

Sex Differences in Discrimination Behavior and Orbitofrontal Engagement During Context-Gated Reward Prediction

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