Sex Differences in Selecting Between Food and Cocaine Reinforcement are Mediated by Estrogen

Abstract

Cocaine-dependent women, relative to their male counterparts, report shorter cocaine-free periods and report transiting faster from first use to entering treatment for addiction. Similarly, preclinical studies indicate that female rats, particularly those in the estrus phase of their reproductive cycle, show increased operant responding for cocaine under a wide variety of schedules. Making maladaptive choices is a component of drug dependence, and concurrent reinforcement schedules that examine cocaine choice offers an animal model of the conditions of human drug use; therefore, the examination of sex differences in decision-making may be critical to understanding why women display a more severe profile of cocaine addiction than men. Accordingly, we assessed sex and estrous cycle differences in choice between food (45 mg grain pellets) and intravenous cocaine (0.4 or 1.0 mg/kg per infusion) reinforcement in male, female (freely cycling), and ovariectomized (OVX) females treated with either estrogen benzoate (EB; 5 μg per day) or vehicle. At both cocaine doses, intact female rats choose cocaine over food significantly more than male rats. However, the estrous cycle did not impact the level of cocaine choice in intact females. Nevertheless, OVX females treated with vehicle exhibited a substantially lower cocaine choice compared with those receiving daily EB or to intact females. These results demonstrate that intact females have a greater preference for cocaine over food compared with males. Furthermore, this higher preference is estrogen-dependent, but does not vary across the female reproductive cycle, suggesting that ovarian hormones regulate cocaine choice. The present findings indicate that there is a biological predisposition for females to forgo food reinforcement to obtain cocaine reinforcement, which may substantially contribute to women experiencing a more severe profile of cocaine addiction than men.

Choosing Under the Influence: A Drug-Specific Mechanism by Which the Setting Controls Drug Choices in Rats

“…Indeed, all else being equal, merely shortening the interchoice interval from 10 to 1 min was sufficient to make rats shift their choice from saccharin to cocaine within one single 30-trial choice session. This setting-specific control of cocaine choices in the same rats and at the same dose of cocaine (ie, 0.25 mg per injection) confirms previous research (Kerstetter et al, 2012) and helps to resolve current discrepancies across cocaine choice studies in rats, as explained in the Introduction Thomsen et al, 2013).…”

“…This hypothesis is supported by a recent choice study that uniquely manipulated the duration of the interchoice interval while keeping all else equal. As expected, when the interchoice interval was sufficiently shortened to allow the drug influence at the time of choice, most rats shifted from sweet reward to cocaine almost exclusively (Kerstetter et al, 2012).…”

“…There is growing awareness that such lack of options may limit the validity of this research for understanding drug addiction as a drug use disorder (Ahmed, 2005(Ahmed, , 2010Ahmed et al, 2013;Alexander and Hadaway, 1982;Cantin et al, 2010;Caprioli et al, 2015b;Carroll et al, 1989;Kerstetter et al, 2012;Le Sage, 2009;Lenoir et al, , 2013Liu and Grigson, 2005;Perry et al, 2013;Thomsen et al, 2013;Tunstall and Kearns, 2013;Zernig et al, 2013). Indeed, when there is no valuable alternative to the drug, drug self-administration may merely reflect a normal reaction to the lack of choice as opposed to reflecting a disordered behavior caused by an underlying dysfunction (Ahmed, 2010;Ahmed et al, 2013;Hyman and Malenka, 2001).…”

“…This is particularly striking in studies involving a choice between cocaine and sweet reward. In most of these studies, virtually all rats rapidly and almost completely stopped drug use in favor of the competing option (Cantin et al, 2010;Carroll and Lac, 1993;Carroll et al, 1989;Kerstetter et al, 2012;Le Sage, 2009;Lenoir et al, , 2013Madsen and Ahmed, 2015;Perry et al, 2013;Tunstall and Kearns, 2013;Tunstall et al, 2014). Suppression of cocaine use in favor of sweet reward developed even after extended access to cocaine self-administration and could not be surmounted by maximally increasing the dose of cocaine (eg, up to 1.5 mg per injection) (Cantin et al, 2010;.…”

Effects of drugs of abuse on hippocampal plasticity and hippocampus-dependent learning and memory: contributions to development and maintenance of addiction

“…In support of this hypothesis, studies have shown that laboratory rodents learn to self-administer cocaine (e.g., Richardson and Roberts 1996;España et al 2010) and associate a specific context with cocaine reward (e.g., Spyraki et al 1982;Vidal-Infer et al 2012) remarkably quickly. The rewarding effects of cocaine are so powerful that a number of studies have shown that an especially addiction-prone subset of laboratory animals trained to selfadminister cocaine prefer cocaine over feeding and mating and compulsively self-administer cocaine at fatal rates (Deneau et al 1969;Lenoir et al 2007;Kerstetter et al 2012;Perry et al 2013). This suggests that the coupling of cocaine's procognitive effects with overstimulation of the reward system may result in dysregulated behavioral outcomes rather than enhancement of behavioral control.…”