Impact of Sex and Gonadal Hormones on Cocaine and Food Reinforcement Paradigms

Abstract

IntroductionWomen, compared to men, face a more severe pattern of cocaine dependence. Sex differences in the profile of cocaine dependence have indicated that women, relative to men, transition faster from first use to entering treatment [1], which may be explained by women abusing cocaine via more addictive routes more quickly and reporting a more rapid progression of drug dependence [2]. In addition, cocaine dependent women report shorter cocaine-free periods [3], have an increased incidence of relapse [4], experience greater cocaine craving in response to psychological and physical stressors [5], and have a greater tendency to report relapses with an impulsive quality [6]. There is also evidence of sex differences in the profile of dependence on other drugs such as prescription opiates [7] and methamphetamine [8,9] that have indicated a more severe impact of substance abuse in women compared to men, including exacerbation of cognitive impairments associated with stimulant dependence [9]. Compared to cocaine-dependent men, cocaine-dependent women are also more likely to attempt suicide [10,11] and addicted women exhibit poorer nutrition than addicted men [12]. Together, these findings indicate that a critical aspect in sex differences in addiction may include altered evaluation of the choice to engage in drug taking versus nondrug experiences, such as food and other pleasurable activities.Sex differences in psychostimulant dependence may be explained by the effects of gonadal hormones, including fluctuations across the female reproductive cycle. For women, the subjective experience of using cocaine is more or less pleasurable, depending on what phase of the menstrual cycle they are in at the time of drug intake [13,14]. In addition, progesterone administration can diminish the positive effects of cocaine in women, but not men [15,16]. Accordingly, evidence from human laboratory studies indicates that there are roles for hormones in cocaine responsiveness and that the ability of hormones to modulate cocaine responsiveness is sexually differentiated. However, the direction of sex differences in stimulant reinforcement can sometimes be dose-dependent. For instance, one study that AbstractMen and women express sexually dimorphic patterns of cocaine abuse, such that women progress faster from initially trying cocaine to becoming dependent upon the drug and display a greater incidence of relapse. Sex differences in response to cocaine are also seen in the laboratory in both humans and animal models. In this review, animal models of cocaine abuse that have reported sex differences in appetitive reinforcement are discussed. In both human and animal studies, sex differences in the subjective and behavioral effects of cocaine are often related to the female reproductive cycle and ovarian hormones. As a comparison, food reinforcement studies have shown the opposite profile of sex differences and the impact of sex steroids on food intake and response rate. In contrast, limited attention has been given to "choice" models i...

Sex differences, gender and addiction

“…The females that choose cocaine also do this sooner than the males that ultimately choose cocaine (Perry et al 2013b). Other investigators have also shown that more females choose cocaine over a food reinforce compared with males (Kerstetter et al 2012; Kerstetter and Kippin 2011). …”

“…In these studies animals are considered to exhibit addiction-like behavior if they continue to take a drug when receiving an aversive mild shock, exhibit high levels of responding on a progressive ratio schedule, and continue to respond for the drug under conditions when drug is not available. A few studies have examined the proportion of female rats that develop addiction-like behavior in the laboratory; in these studies where males and females are allowed to choose cocaine or a food reward, more females than males choose cocaine and females exhibit higher responding for cocaine than do males (Perry et al, 2013b;Kerstetter et al, 2012;Kerstetter and Kippin, 2011).…”

Mouse model systems to study sex chromosome genes and behavior: Relevance to humans

“…In contrast to the pain literature, sex differences in addiction are well documented, although not always in the same directions when comparing rats, mice and humans (Anker and Carroll, 2011; Kerstetter and Kippin, 2011). In a test of conditioned habit formation for a food reward (Quinn et al , 2007), XX (all studies in the MF1 FCG) mice regardless of gonadal sex formed the habit more quickly than XY mice.…”

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

“…Female rats exhibit enhanced responding to psychostimulants in multiple paradigms in a manner both dependent and independent of ovarian sex hormones (Hu et al 2004;Jackson et al 2006). In ovariectomized rats, E 2 enhances the sensitization of cocaine-induced locomotor behavior and CPP (Segarra et al 2010), self-administration of cocaine on both fixed and progressive ratio schedules of reinforcement (Lynch and Taylor 2005;Zhao and Becker 2010), and preference for cocaine over food reinforcement in a discrete trials procedure (Kerstetter and Kippin 2011), and lowers thresholds for electrical brain stimulation of the ventral tegmental area (Galankin et al 2010). Thus, E 2 -enhanced expression of CPP could be interpreted as further evidence in females of "enhanced abuse liability to cocaine," yet this interpretation is at odds with the finding that E 2 also enhanced extinction of drug seeking.…”

“…A substantial literature supports that estrogens mediate the enhancement of drug seeking observed in females (Febo et al 2002;Larson et al 2007;Segarra et al 2010;Kerstetter and Kippin 2011), but little is known regarding the role of estrogens during treatment. Preclinically, treatment is modeled through extinction learning, which results in the formation of a new inhibitory memory that suppresses drug seeking Torregrossa and Taylor 2012).…”