Effects of menstrual cycle phase on cocaine self-administration in rhesus macaques
Highlights
► Female rhesus macaques and humans have similar menstrual cycles. ► Cocaine self-administration did not vary systematically across the menstrual cycle. ► Future studies should manipulate behavioral contingencies to detect subtle changes.
Introduction
Though epidemiological findings report that cocaine use continues to be more prevalent among men than women (Cotto et al., 2010), the rates of new initiates to cocaine use among the adolescent population have been increasing among females, while remaining constant among males (SAMHSA, 2008). In conjunction with these statistics, women exhibit a more rapid progression from first use to cocaine-related substance use disorders (Carroll et al., 2002, Cotto et al., 2010) and are less successful when seeking treatment for these disorders relative to men due to low rates of treatment retention (Siqueland et al., 2002) or high rates of relapse to cocaine use (Hyman et al., 2007). Over the last decade, complementary preclinical data in laboratory animals have illustrated sex-dependent behavioral effects of cocaine. Many of these studies have demonstrated that laboratory animal models used to assess cocaine's abuse liability can be implemented to further understand the neuroendocrine basis for sex-dependent differences among the human cocaine-using population.
Cocaine self-administration studies in laboratory animals have probed this question by directly comparing behavior between males and females. Overall, these findings indicate that female rats demonstrate greater sensitivity to cocaine's reinforcing effects relative to males with shorter acquisition times (Carroll et al., 2002, Lynch and Carroll, 1999), higher rates of cocaine self-administration (Lynch and Taylor, 2004, Lynch and Taylor, 2005, Roberts et al., 1989), and greater resistance to extinction (Kerstetter et al., 2008, Lynch and Carroll, 2000). Studies examining the role of gonadal hormones on cocaine-maintained behaviors found that females demonstrate the greatest sensitivity to cocaine's reinforcing effects (Feltenstein et al., 2009, Hecht et al., 1999, Roberts et al., 1989) and resistance to extinguish responding previously paired with cocaine (Kerstetter et al., 2008, Kippin et al., 2005) during estrus, when circulating estradiol levels are at their highest and progesterone levels are at their lowest. Specifically, plasma progesterone levels appear to predict the behavioral effects of cocaine such that responding was inversely correlated with progesterone plasma levels, with lower progesterone levels predicting greater responding (Feltenstein and See, 2007). Other studies have shown that exogenous progesterone, and its metabolite, allopregnanolone, attenuate acquisition of cocaine self-administration, escalation of cocaine self-administration, and reinstatement of cocaine-seeking (Anker et al., 2007, Feltenstein et al., 2009, Hu and Becker, 2008, Jackson et al., 2006, Larson et al., 2005, Larson et al., 2007, Lynch et al., 2001).
Controlled human laboratory studies have also investigated the extent to which cocaine's effects vary between males and females. Findings from early human studies investigating sex-dependent differences in the subjective effects of cocaine have been mixed (Evans et al., 1999, Haney et al., 1998, Kosten et al., 1996), challenging the generalizability of cocaine's sex-dependent differences observed in rodent models. However, these studies varied with respect to the route of cocaine administered and they did not control for menstrual cycle phase. Several studies have directly investigated the extent to which menstrual cycle phase contributes to sex differences in the subjective response to cocaine (Collins et al., 2007, Evans and Foltin, 2006a, Evans et al., 2002, Lukas et al., 1996, Mendelson et al., 1999, Sofuoglu et al., 1999), but again, the results have been inconsistent, particularly among studies that administered intranasal cocaine (Collins et al., 2007, Lukas et al., 1996). In contrast, studies with smoked cocaine have revealed a clearer contribution of menstrual cycle phase to cocaine's subjective effects. The subjective effects of smoked cocaine are similar between men and women tested during the follicular phase, when estradiol levels are high and progesterone levels are low (Evans and Foltin, 2006a, Sofuoglu et al., 1999), whereas during the luteal phase (when progesterone levels are high) the subjective response to smoked cocaine is decreased relative to females tested during the follicular phase (Evans and Foltin, 2006a, Evans et al., 2002, Sofuoglu et al., 1999; but see Reed et al., 2011) or to men (Evans and Foltin, 2006a, Sofuoglu et al., 1999). Further, administration of exogenous progesterone decreased subjective responses to smoked cocaine in females during the follicular phase (Evans and Foltin, 2006a, Sofuoglu et al., 2002), but not in men (Evans and Foltin, 2006a). Exogenous progesterone also decreased the subjective ratings of ‘high’ produced by intravenous cocaine in a sample of men (n = 6) and women (n = 4) tested during the follicular phase (Sofuoglu et al., 2004). Despite these differences in subjective response to cocaine, and in contrast to the preclinical literature in rodents, no studies in humans have observed differences in cocaine self-administration as a function of sex (Lynch et al., 2008, Sofuoglu et al., 1999, Sofuoglu et al., 2004), menstrual cycle phase (Reed et al., 2011, Sofuoglu et al., 1999), or progesterone administration (Reed et al., 2011, Sofuoglu et al., 2004). Thus, it remains unclear whether differences in the subjective response to cocaine between men and women, possibly due to naturally occurring fluctuations of gonadal hormone levels, contribute to differences in the reinforcing effects of cocaine. There are inherent limitations of human-subjects research, such as constraints on study length, restriction on the number and range of cocaine doses that can be tested, and inability to control for variability between participants that present obstacles for systematically investigating the role of gonadal hormones on cocaine's behavioral effects in humans. To overcome these limitations, the current study investigated the effects of menstrual cycle phase on cocaine self-administration in non-human primates, a species that can perhaps provide the most generalizable findings to predict factors that contribute to human drug abuse and dependence (Weerts et al., 2007).
Given the similarity in menstrual cycle in terms of duration and hormonal fluctuations between female macaques and humans (Appt, 2004, Shimizu, 2005), macaques are an ideal species to use for attempting to elucidate the role of fluctuations of gonadal across the menstrual cycle on cocaine reinforcement. Despite these similarities between humans and non-human primates, only 3 studies, all from the same laboratory, have been conducted to evaluate the reinforcing effects of intravenous cocaine in non-human primates as a function of sex, menstrual cycle phase, and administration of exogenous gonadal hormones (Mello et al., 2007, Mello et al., 2008, Mello et al., 2011). In one study (Mello et al., 2007), 4 gonadally intact, cycling female and 2 gonadally intact male cynomolgus monkeys (Macaca fascicularis) self-administered intravenous cocaine using a progressive ratio schedule of reinforcement. In that study, menstrual cycle phase did not consistently alter responding in female monkeys, although females reached a higher progressive ratio breakpoint than males for all doses tested, demonstrating a clear sex difference. Mello et al. also showed that exogenous estradiol failed to consistently affect cocaine self-administration in female rhesus monkeys (2 gonadally intact and 2 ovariectomized; Mello et al., 2008), whereas exogenous progesterone decreased intravenous cocaine self-administration of 0.01 mg/kg/injection in female rhesus monkeys (4 gonadally intact and 1 ovariectomized: Mello et al., 2011). These findings are important since they bridge the results in rodents with the results in humans. Therefore, the present study had two objectives. Since the majority of non-human primate research related to the reinforcing effects of cocaine have been conducted in rhesus monkeys (Mello and Negus, 1996), the first objective was to extend the results obtained in female cynomolgus monkeys (Mello et al., 2007) to rhesus monkeys, by determining whether cocaine's reinforcing effects varied as a function of menstrual cycle phase using a progressive ratio schedule of cocaine self-administration. The second objective was to relate these findings to studies conducted in human female cocaine abusers (Evans and Foltin, 2006a, Evans et al., 2002, Reed et al., 2011).
Section snippets
Subjects
Five adult female rhesus monkeys (Macaca mulatta), weighing 6.0 to 10.0 kg, were housed unrestrained as described below for the duration of the study in a room that was maintained on a 12 h light/dark cycle, with lights on at 7 AM. Each day, monkeys received fruit, a daily vitamin, and monkey chow to maintain stable body weight; approximately 7–9 chow (105–135 g; High protein monkey diet #5047, 3.37 kcal/g; LabDiets®, PMI Feeds, Inc., St. Louis, MO). In addition, monkeys periodically received
Menstrual cyclicity and plasma hormone levels
Table 1 depicts the range and average duration of each monkey's menstrual cycles and the number of ovulatory cycles over which cocaine self-administration was tested. Across the group, cocaine self-administration took place over 16.8 ± 3.1 ovulatory cycles with an average cycle length of 29.4 ± 0.4 days. Anovulatory cycles were observed in 4 of the 5 monkeys tested based upon plasma hormone levels and cycle length (66U, RQ205, and 44U2 exhibited 1 anovulatory cycle, and 7CX exhibited 5 anovulatory
Discussion
The current study was designed to assess the impact of menstrual cycle phase on the reinforcing effectiveness of cocaine in healthy, regularly cycling female rhesus monkeys. Though there is considerable evidence derived from rodent self-administration studies to show that both phase and exogenous sex-hormone administration affects cocaine's reinforcing effects, few studies have investigated these effects in non-human primates, a species that shares a similar menstrual cycle with humans.
Conclusion
The results from the current study in rhesus monkeys indicate that normal fluctuations of estradiol and progesterone associated with the menstrual cycle do not alter cocaine's reinforcing effects. Although cocaine self-administration did not change as a function of menstrual cycle phase in the current study, strengthening stimulus control and manipulating experimental variables to increase experimental sensitivity may further enhance our understanding of the subtle effects of gonadal hormones
Acknowledgments
This research was supported by grant nos. R01 DA012675 (SME) and K01 DA027755 (ZDC) from the National Institute on Drug Abuse (NIDA). NIDA had no role in study design or in the decision to submit the paper for publication. NIDA also had no role in the collection, analysis and interpretation of data in the writing of the report. We acknowledge and appreciate the technical support provided by April Modrzakowski, Julian Perez, Angel Ramirez, and Jean Willi. We also thank Girma Asfaw, Robert
References (52)
- et al.
Intranasal cocaine in humans: effects of sex and menstrual cycle
Pharmacol. Biochem. Behav.
(2007) - et al.
Gender effects on drug use, abuse, and dependence: a special analysis of results from the National Survey on Drug Use and Health
Gend. Med.
(2010) - et al.
Pharmacokinetics of repeated doses of intravenous cocaine across the menstrual cycle in rhesus monkeys
Pharmacol. Biochem. Behav.
(2006) - et al.
Limited sex differences in response to “binge” smoked cocaine use in humans
Neuropsychopharmacology
(1999) - et al.
Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle
Drug Alcohol Depend.
(2007) - et al.
Attenuation of cocaine-seeking by progesterone treatment in female rats
Psychoneuroendocrinology
(2009) - et al.
Acquisition of cocaine self-administration in ovariectomized female rats: effect of estradiol dose or chronic estradiol administration
Drug Alcohol Depend.
(2008) - et al.
Gender differences in response to intranasal cocaine administration to humans
Biol. Psychiatry
(1996) - et al.
Effect of short- vs. long-term estrogen on reinstatement of cocaine-seeking behavior in female rats
Pharmacol. Biochem. Behav.
(2005) - et al.
Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats
Pharmacol. Biochem. Behav.
(2001)
Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures
Neuropsychopharmacology
Cocaine pharmacokinetics in men and in women during the follicular and luteal phases of the menstrual cycle
Neuropsychopharmacology
Effects of follicular-phase cocaine administration on menstrual and ovarian cyclicity in rhesus monkeys
Am. J. Obstet. Gynecol.
The effects of oral micronized progesterone on smoked cocaine self-administration in women
Horm. Behav.
Effects of progesterone treatment on smoked cocaine response in women
Pharmacol. Biochem. Behav.
Effects of progesterone treatment on cocaine responses in male and female cocaine users
Pharmacol. Biochem. Behav.
Effects of progesterone on the reinstatement of cocaine-seeking behavior in female rats
Exp. Clin. Psychopharmacol.
Usefulness of the monkey model to investigate the role of soy in postmenopausal women's health
ILAR J.
Intravenous cocaine and heroin self-administration in rats selectively bred for differential saccharin intake: phenotype and sex differences
Psychopharmacology (Berl.)
Does the response to cocaine differ as a function of sex and hormonal status in human and non-human primates?
Horm. Behav.
Pharmacokinetics of intravenous cocaine across the menstrual cycle in rhesus monkeys
Neuropsychopharmacology
Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men
Neuropsychopharmacology
The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women
Psychopharmacology (Berl.)
Effects of pergolide on intravenous cocaine self-administration in men and women
Psychopharmacology (Berl.)
Changes in progressive ratio responding for intravenous cocaine throughout the reproductive process in female rats
Dev. Psychobiol.
Progressive ratio as a measure of reward strength
Science
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