The influence of sex and reproductive cycle on cocaine-induced behavioral and neurobiological alterations: a review

Rosário, Bárbara dos Anjos; SantanaNazaré, Maria de Fátima; Souza, Daniel Vitor de; Sueur-Maluf, Luciana Le; Estadella, Débora; Ribeiro, Daniel Araki; Viana, Milena de Barros

doi:10.1007/s00221-022-06479-4

Cited by 3 publications

(3 citation statements)

References 85 publications

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“…Preclinical animal studies, primarily conducted in rats, similarly indicate an enhanced sensitivity in females to the positive reinforcing effects of cocaine. For example, in gonad-intact rats, females acquired cocaine selfadministration faster and worked harder to obtain infusions of cocaine than males [6][7][8]. Mechanistic studies of this enhanced sensitivity in females have focused almost exclusively on gonadal hormones, particularly estradiol.…”

Section: Introductionmentioning

confidence: 99%

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Le¹,

Lynch²,

Rissman³

2023

Neuroendocrinology

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Introduction- Women are more vulnerable to cocaine’s reinforcing effects and have a more rapid course to addiction after initial cocaine use as compared to men. Studies in rodents similarly indicate an enhanced sensitivity to the reinforcing effects of cocaine in females versus males. Levels of estradiol (E2) are correlated with vulnerability to the rewarding actions of cocaine. Here we asked if sex chromosome complement (SCC) influences vulnerability to cocaine use. Methods- We used the four core genotype (FCG) mouse that produces gonadal males and females with either XX or XY SCC. Mice were gonadectomized and implanted with either an estradiol (E2) or cholesterol-filled pellet. This allowed us to determine effects of SCC in the absence (cholesterol treated) and presence of tonic high physiological hormone levels (estradiol). Acquisition of cocaine self-administration was determined over a 12-day period using an escalated dose procedure (0.3 mg/kg/infusion, sessions 1-6; 0.6 mg/kg/infusion, sessions 6-12). Results- Without estradiol treatment, a greater percentage of castrated XY mice acquired cocaine self-administration and did so at a faster rate than XX castrates and ovariectomized XY females. These same XY males acquired sooner, infused more cocaine, and directed more nose pokes to the rewarded nose-poke hole than XX castrates and XY males receiving E2. Conclusion- Our results suggest that in gonadal male mice, SCC and estradiol can modulate the reinforcing effects of cocaine which may influence the likelihood of cocaine use.

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Section: Introductionmentioning

confidence: 99%

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Le¹,

Lynch²,

Rissman³

2023

Neuroendocrinology

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“…Sex differences in behavioral activities related to animal models of psychostimulant use and dependence have been found in rodent tests of psychostimulant self-administration [ 33 ]. Studies have shown that female rats are more likely to self-administer cocaine at greater rates compared to male rats during long periods with access to cocaine [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors

et al. 2023

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Psychostimulant use disorders (PSUD) affect a growing number of men and women and exert sizable public health and economic burdens on our global society. Notably, there are some sex differences in the onset of dependence, relapse rates, and treatment success with PSUD observed in preclinical and clinical studies. The subtle sex differences observed in the behavioral aspects of PSUD may be associated with differences in the neurochemistry of the dopaminergic system between sexes. Preclinically, psychostimulants have been shown to increase synaptic dopamine (DA) levels and may downregulate the dopamine transporter (DAT). This effect is greatest in females during the high estradiol phase of the estrous cycle. Interestingly, women have been shown to be more likely to begin drug use at younger ages and report higher levels of desire to use cocaine than males. Even though there is currently no FDA-approved medication, modafinil, a DAT inhibitor approved for use in the treatment of narcolepsy and sleep disorders, has shown promise in the treatment of PSUD among specific populations of affected individuals. In this review, we highlight the therapeutic potential of modafinil and other atypical DAT inhibitors focusing on the lack of sex differences in the actions of these agents.

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“…For cocaine use disorder, results from animal studies suggest that in both sexes the administration of progesterone may serve as a potential treatment, whereas estradiol leads to an increase in the risk of addictive behaviors (11,12). In female and male rodents, progesterone attenuates the reinforcing effects of cocaine with reduced acquisition, escalation, and reinstatement of self-administration (13).…”

Section: Introductionmentioning

confidence: 99%

Progesterone/Estradiol Ratio Is Related to Real-Life Alcohol Consumption in Alcohol Use Disorder in a Sex- and Menstrual Cycle Phase-Dependent Manner

Hoffmann

Gerhardt

Mühle

et al. 2022

Preprint

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Background: Alcohol use disorder (AUD) is a critical public health issue with sex-specific characteristics and the need for a better mechanistic understanding. Initial evidence suggests that progesterone can reduce alcohol intake, while estradiol leads to an increase. However, we lack knowledge about how progesterone relative to estradiol influences alcohol use patterns in females and males with AUD. Methods: This multicenter within-subject study analyzed data on real-life alcohol use (21,438 intensively-sampled smartphone entries), menstrual cycle, and serum progesterone/estradiol ratios (677 blood samples) gathered during a 12-month follow-up in 74 naturally cycling females and 285 males with AUD (mean age: 29.7 and 37.8 years, respectively; data collection: 2020-2022). We used multilevel modelling to identify changes in alcohol use and progesterone/estradiol ratios across the menstrual cycle in females and associations between progesterone/estradiol ratios and alcohol use in males. Results: During the late luteal phase, females showed 0.6- to 0.8-fold lower (predicted) probabilities of binge drinking and 2.8- to 5.6-fold higher mean progesterone/estradiol ratios compared to the menstrual, follicular, and ovulatory phases. Similarly, in males, an increase of 10 units in the progesterone/estradiol ratio was related to 8 and 9% lower probabilities of binge drinking and any alcohol use, respectively. Conclusions: Based on ecologically valid results, this study reveals that higher progesterone/estradiol ratios can protect against problematic alcohol use in females and males with AUD. Therefore, the progesterone/estradiol ratio is a promising treatment target. Translated into clinical practice, our results also indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

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The influence of sex and reproductive cycle on cocaine-induced behavioral and neurobiological alterations: a review

Cited by 3 publications

References 85 publications

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Sex Chromosome Complement and Estradiol Modify Cocaine Self-Administration Behaviors in Male Mice

Are There Prevalent Sex Differences in Psychostimulant Use Disorder? A Focus on the Potential Therapeutic Efficacy of Atypical Dopamine Uptake Inhibitors

Progesterone/Estradiol Ratio Is Related to Real-Life Alcohol Consumption in Alcohol Use Disorder in a Sex- and Menstrual Cycle Phase-Dependent Manner

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