Exogenous Progesterone Attenuates the Subjective Effects of Smoked Cocaine in Women, but not in Men

New York State Psychiatric Institute, Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 04/2006; 31(3):659-74. DOI: 10.1038/sj.npp.1300887
Source: PubMed


In a previous study, we showed that the positive subjective effects of cocaine were higher during the follicular phase compared to the luteal phase of the menstrual cycle. The purpose of the present study was to determine if exogenously administered progesterone during the follicular phase in females would attenuate the response to cocaine compared to the normal follicular phase, thus making the response to cocaine similar to the luteal phase. To address the role of sex differences, males were also administered exogenous progesterone during one inpatient stay. In all, 11 female and 10 male non-treatment-seeking cocaine smokers participated. Females had three inpatient stays: one during a normal follicular phase, one during a normal luteal phase, and one during a follicular phase when exogenous progesterone was administered. Males had two inpatient stays: one when exogenous progesterone was administered and the other when placebo was administered. During each inpatient admission, there were four smoked cocaine administration sessions: participants were administered six doses of cocaine (0, 6, 12, or 25 mg cocaine base) at 14 min intervals. Smoked cocaine increased heart rate, blood pressure and several subjective effects such as 'good drug effect' and 'drug quality' cluster scores. Administration of progesterone during the follicular phase in women attenuated the positive subjective effects of cocaine, whereas only minimal changes were observed in men. These results indicate that progesterone modulates the response to cocaine in women and suggests that fluctuations in endogenous progesterone levels account for some of the sex differences observed in humans.

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    • "In humans, reports regarding the treatment efficacy of P in males have been mixed. While one study found a significant attenuation of positive subjective effects and cardiovascular responses in men (Sofuoglu et al. 2004), another found little to no effect on cocaine's subjective effects (Evans and Foltin 2006) and cocaine use (Sofuoglu et al. 2007) and only dose-dependent decreases in cardiovascular responses to cocaine (Evans and Foltin 2006) in males. These equivocal findings are in accordance with rodent studies demonstrating P treatment as both effective (Romieu et al. 2003) and ineffective (Russo et al. 2010) in decreasing cocaine-conditioned place preference in males. "
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    ABSTRACT: Individually, both treatment with progesterone and concurrent access to an exercise wheel reduce cocaine self-administration under long-access conditions and suppress cocaine-primed reinstatement in female rats. In the present study, wheel running and progesterone (alone and combined) were assessed for their effects on reinstatement of cocaine-seeking primed by yohimbine, cocaine, and cocaine-paired cues. Male and female rats were implanted with an intravenous catheter and allowed to self-administer cocaine (0.4 mg/kg/inf, iv) during 6-h sessions for 10 days. Subsequently, the groups of male and female rats were each divided into two groups that were given concurrent access to either a locked or unlocked running wheel under extinction conditions for 14 days. Next, all four groups were tested in a within-subjects design for reinstatement of cocaine-seeking precipitated by separate administration of cocaine-paired stimuli, yohimbine, or cocaine or the combination of yohimbine + cocaine-paired stimuli or cocaine + cocaine-paired stimuli. These priming conditions were tested in the presence of concurrent wheel access (W), pretreatment with progesterone (P), or both (W + P). In agreement with previous results, females responded more for cocaine than males during maintenance. Additionally, concurrent wheel running attenuated extinction responses and cocaine-primed reinstatement in females but not in males. Across all priming conditions, W + P reduced reinstatement compared to control conditions, and for cocaine-primed reinstatement in male rats, the combined W + P treatment was more effective than W or P alone. Under certain conditions, combined behavioral (exercise) and pharmacological (progesterone) interventions were more successful at reducing cocaine-seeking behavior than either intervention alone.
    Full-text · Article · Mar 2014 · Psychopharmacology
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    • "Across species, the fluctuation of reproductive hormones across the menstrual cycle has been shown to alter the effects of psychoactive drugs including cocaine (Sofuoglu et al., 1999, 2002; Evans et al., 2002; Evans and Foltin, 2006; Mello et al., 2007; Lynch et al., 2008) and opioids (see Craft, 2003 for review). During the follicular, or estrus, phase when progesterone is low and estradiol is high, females exhibit higher rates of cocaine and opioid self-administration relative to males (Evans and Foltin, 2006; Lynch et al., 2008). The behavioral effects of cannabinoids are similarly modulated by fluctuating endogenous ovarian "
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    ABSTRACT: Women exhibit an accelerated progression from first cannabis use to cannabis use disorder (CUD) and show pronounced negative clinical issues related to CUD relative to men. Whether sex-dependent differences in cannabis' direct effects contribute to the heightened risk in women is unknown. This analysis directly compared cannabis' abuse-related subjective effects in men and women matched for current cannabis use. Data from four double-blind, within-subject studies measuring the effects of active cannabis (3.27-5.50% THC, depending on study) relative to inactive cannabis (0.00% THC) were combined for this analysis. Data from equal numbers of men and women from each study matched for current cannabis use were pooled (total n=35 men; 35 women); cannabis' effects were analyzed according to cannabis condition (active versus inactive) and sex. Active cannabis produced more robust subjective effects associated with abuse liability ('Good,' 'Liking,' 'Take Again') and intoxication ('High,' 'Stimulated') relative to inactive cannabis (p≤0.0001). Women reported higher ratings of abuse-related effects ['Take Again' and 'Good' (p≤0.05)] relative to men under active cannabis conditions but did not differ in ratings of intoxication. Active cannabis increased heart rate (p≤0.0001) equally for both sexes. The results from this study suggest that when matched for cannabis use, women are more sensitive to the subjective effects related to cannabis' abuse liability relative to men, which may contribute to the enhanced vulnerability to developing CUD. Thus, sex is an important variable to consider when assessing the development of CUD.
    Full-text · Article · Jan 2014 · Drug and alcohol dependence
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    • "The sex steroid milieu also plays a major role in modulating the effects of drugs of abuse. The consensus from previous studies is that progesterone attenuates the subjective effects of cocaine (Anker and Carroll, 2010; Evans and Foltin, 2006; Reed et al., 2011) whereas estradiol exacerbates drugassociated responses (Evans et al., 2002). "
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    ABSTRACT: Preclinical studies show that estradiol enhances sensitization to cocaine in females by mechanisms not fully understood. These studies consistently show that ovariectomized (OVX) rats exhibit little or no sensitization to cocaine compared to OVX rats administered estradiol. In this study we varied the dose of cocaine (10, 15, and 30mg/kg), the length of cocaine treatment (from 5 to 10days) and the context of cocaine injections to determine if these factors play a role on estradiol's effects on cocaine sensitization. Because OVX rats are hormonally compromised, they are not representative of the natural state of the animal, and thus the physiological context of these studies remains unclear. To address this issue, we blocked ERs in gonadally intact females by icv administration of the antiestrogen ICI-182,780. Varying the dose or length of exposure to cocaine does not alter estradiol's effect on cocaine sensitization. In contrast, a highly context-dependent sensitization protocol results in robust sensitization even in OVX rats. Interestingly, using this protocol, sensitization in OVX rats diminished with time, suggesting that estradiol is necessary for the maintenance of cocaine sensitization. Blocking brain ERs with ICI completely abolishes the development and expression of cocaine sensization in gonadally intact female rats, even when tested in a highly context-dependent sensitization protocol. Given these findings, we propose that activation of brain ERs is required for the development and maintenance of sensitization and CPP.
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