Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates?

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Abstract

Stimulant abuse continues to be a growing problem among women. Over the last 10–15 years, an increasing number of studies have focused on factors that may be implicated in stimulant abuse in women as compared to men, including the role of hormonal fluctuations across the menstrual cycle. Numerous preclinical studies have documented that female rodents are more sensitive than male rodents to the behavioral effects of stimulant administration and the hormone estradiol is involved in the enhanced response to stimulants observed in females. In contrast, fewer studies have been conducted in humans and non-human primates addressing the role of sex and gonadal hormones on the effects of cocaine. This review paper presents a recent update on data collected in our Human Cocaine Challenge Laboratory and our Non-human Primate Laboratory, including analysis of cocaine pharmacokinetics, sex differences, the menstrual cycle, and the role of progesterone in modulating the response to cocaine. Our studies indicate that there is minimal evidence that the response to intranasal cocaine varies across the menstrual cycle or between men and women. In contrast, the response to smoked cocaine is greater in the follicular phase than the luteal phase and differences between men and women generally only emerge when men are compared to women in the luteal phase. In terms of potential hormonal mechanisms for these differences, the hormone progesterone attenuates the subjective response to cocaine. With respect to cocaine self-administration, there are minimal changes across the menstrual cycle in both humans and non-human primates. Thus, there is converging evidence across a range of species that the behavioral effects of cocaine (1) differ between males and females, (2) differ in relation to hormonal fluctuations, (3) can be attenuated by progesterone (at least in females), and (4) do not appear to be related to differences in cocaine pharmacokinetics.

Introduction

Cocaine abuse continues to be a growing problem among women, with the gender gap narrowing with respect to new cocaine use, even among those 12–17 years of age (SAMHSA, 2008). Although men are still more likely to be cocaine dependent than women, women exhibit a more rapid progression of the illness and they have a higher incidence of comorbid psychiatric disorders (McCance-Katz et al., 1999, Najavits and Lester, 2008, O'Brien and Anthony, 2005, Sinha and Rounsaville, 2002). These sex differences may contribute to women relapsing (Hyman et al., 2008) or dropping out of treatment sooner than men (Siqueland et al., 2002). These results parallel preclinical animal models using rodents showing that females are more vulnerable to the abuse-related effects of cocaine than males (see reviews by Becker et al., 2001, Festa and Quiñones-Jenab, 2004, Lynch et al., 2002, Mello and Mendelson, 2002).

This review paper will present a recent update using human and non-human primate models to assess differences in the response to cocaine including pharmacokinetics, sex differences, the menstrual cycle, and the role of progesterone in modulating the response to cocaine, with a specific emphasis on the research endeavors (both published and unpublished) conducted in our Human Cocaine Challenge Laboratory (Marian W. Fischman Behavioral Pharmacology Laboratory) and our Non-human Primate Laboratory. Accordingly, this will not be a comprehensive literature review, but relevant and related published research conducted by other laboratories will be mentioned. All human participants signed consent forms approved by the institutional review boards of the College of Physicians and Surgeons of Columbia University or the New York State Psychiatric Institute and participants were financially compensated. All aspects of animal maintenance and experimental procedures of our non-human primate studies complied with the U.S. National Institutes of Health Guide for Care and Use of Laboratory Animals and were approved by the New York State Psychiatric Institute Animal Care and Use Committee.

Section snippets

Menstrual cycle of human and non-human primates

While the vast majority of research on sex differences and the role of reproductive hormones on the response to cocaine have been conducted in rats, the rat estrous cycle is quite different from the menstrual cycle of humans and laboratory primates. The rat estrous cycle is typically 4 days, separated into four phases: diestrus, proestrus, estrus, and metestrus (for an excellent review comparing the rat estrous cycle and human menstrual cycle, see Lynch et al., 2002). During proestrus, the

Cocaine pharmacokinetics

There is growing evidence, primarily from rodent studies, that there are sex differences in the behavioral responses to cocaine. Further, fluctuations in estradiol and progesterone underlie these behavioral differences that may be related to differences in cocaine pharmacokinetics. Clearly, when investigating and interpreting behavioral differences in response to a drug, whether it is differences between males and females, or differences as a function of hormonal status, it is important to

Subjective response to cocaine: sex and menstrual cycle effects

We and several other research groups have investigated whether there are differences in the subjective response to cocaine between men and women and whether these differences are related to hormonal fluctuations across the menstrual cycle (Collins et al., 2007, Evans et al., 1999, Evans et al., 2002, Evans and Foltin, 2006a, Haney et al., 1998, Kosten et al., 1996, Lukas et al., 1996, Mendelson et al., 1999a, Sofuoglu et al., 1999). As mentioned above, our initial retrospective study that

Cocaine self-administration

In some of the studies mentioned above, including the pharmacokinetic studies in monkeys, we specifically did not use a self-administration or choice procedure in order to ensure that all of the doses were administered. Studies from our laboratory have shown repeatedly that a decrease in the positive subjective effects of cocaine does not necessarily result in a decrease in actual drug taking using cocaine self-administration procedures (Haney and Spealman, 2008). Thus, even if the subjective

Implications

Taken together, there is converging evidence that across a range of species, the behavioral effects of cocaine (1) differ between males and females, (2) differ across the menstrual cycle (or estrus cycle in rodents), (3) can be attenuated by progesterone (at least in females), and (4) do not appear to be related to differences in cocaine pharmacokinetics. Despite the progress made thus far, much more data are still needed to fill in the existing gaps with respect to the possible mechanisms

Acknowledgments

This manuscript was supported by Grants No. DA-08105 (Principal Investigator: Richard W. Foltin), DA-009114 (Principal Investigator: Suzette M. Evans), and DA12675 (Principal Investigator: Suzette M. Evans) from the National Institute on Drug Abuse and grant No. MOI-RR-00645 from the National Institutes of Health. For some of the studies conducted by Evans and colleagues, oral micronized progesterone and matching placebo capsules were generously provided by the Women's International Pharmacy

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