This project continues the work begun in Dr. See’s previous SCOR work investigating conditioned-cue and drug-primed reinstatement of cocaine-seeking in a rodent model of relapse. Recent studies have found that selective pharmacological agents will produce reliable stress-induced reinstatement, in particular the 2-noradrenergic receptor antagonist, yohimbine (Feltenstein and See 2006; Shepard et al. 2004) and corticotropin-releasing factor (CRF) (Shaham et al. 1997). In this project, Dr. See will be exploring sex and estrous cycle differences in stress-induced reinstatement using a novel paradigm of pharmacologic stressors, namely yohimbine and CRF. This approach allows direct activation of stress pathways and the ability to use identical stressors in the animal model and the human clinical laboratory, providing a high degree of homology and integration. The yohimbine stressor will also be used in Research Component #2, which is a human laboratory study. In addition, progesterone and estradiol levels will be measured at the time of testing in both the animal and human projects, based on the intriguing findings concerning progesterone and reinstatement.

The ability of several different agents to block reinstatement produced by different trigger factors in male and female rats, including females at various stages of the estrous cycle will be tested. In particular, the impact of aripiprazole and other novel pharmacotherapies on stress-induced reinstatement in male and female rats will be explored. Clonidine (2-noradrenergic receptor agonist) will be tested with the hypothesis that it will decrease reinstatement of cocaine-seeking in males and females after yohimbine-induced stress, but not conditioned cues. Progesterone pretreatment will be tested with the hypothesis that it will selectively decrease reinstatement of cocaine-seeking after exposure to cocaine priming in female, but not male rats.

This project will explore a novel human laboratory approach to the study of stress-induced craving. This study is a direct extension of the previous SCOR project in which gender differences in the response to a social stressor and cocaine cues in cocaine-dependent individuals were demonstrated. Although gender differences in factors that contribute to relapse in cocaine-dependent individuals have been independently studied (i.e., stress or conditioned cues), the interaction of stress and cues and the effect of ovarian hormones on response have not been directly explored. This study will build on the previous SCOR findings by exploring the impact of a pharmacologic stressor on response to cocaine-related cues in cocaine-dependent men and women and the impact of ovarian hormone status on this response in women. This project will also be important in extending an animal model of pharmacologically-induced stress (yohimbine-induced stress) to a human laboratory setting. This project will further the ability to directly translate findings from an animal model of relapse to an ecologically valid test of relapse in cocaine-dependent humans and explore the impact of hormonal status on response in this model.

A number of studies have demonstrated that individuals with cocaine use disorders are more impulsive than matched controls and that impulsivity may be related to cocaine use. The relationship between impulsivity and stress is largely unexplored, but the increase in noradrenergic activity associated with an acute stress may also increase impulsivity. In this study, an investigation of the interaction of gonadal hormone levels, stress response, and impulsivity is proposed.

The first series of studies in this component will examine sex-related differences in the reinforcing efficacy of nicotine using operant i.v. self-administration procedures. Male and female mice will be compared in studies that manipulate the nicotine unit dosage to establish dose-response functions and systematically vary the work required to obtain nicotine reinforcement through progressive ratio testing. The next series of studies will examine sex-related differences in vulnerability to nicotine relapse, as assessed by operant reinstatement procedures similar to those utilized by Dr. See’s group. Thus, nicotine primed-, cue-, and stress-induced reinstatement of nicotine-seeking will be compared in males, estrus females, and non-estrus females. Progesterone levels at the time of testing will be measured, as well.

This series of studies will examine sex-related differences in sensitivity to pharmacotherapeutic agents with demonstrated efficacy in smoking cessation clinical trials. The ability of buproprion and varenicline to influence nicotine self-administration behavior will be evaluated in male and female mice. For females, subjects will be randomized to begin treatment during different stages of the estrous cycle, enabling direct comparison between males, estrus females, and non-estrus females. Following this, a series of studies examining sex-related differences in the ability of pharmacological treatments to block nicotine reinstatement will be undertaken. Studies will evaluate the ability of both bupropion and varenicline to prevent/attenuate nicotine primed, cue-induced and stress-induced reinstatement of nicotine-seeking behavior in male and female mice. In all of these studies, pharmacological treatment and reinstatement testing will be conducted in male, estrus female, and non-estrus female mice.

This component builds directly upon the results of the previously funded project in systematically investigating the impact of the timing of the quit date within the menstrual cycle (follicular vs. luteal) on relapse to smoking in women. Each subject will participate in cue reactivity and impulsivity testing before the initiation of the smoking cessation trial. Progesterone and estrogen levels at the time of cue reactivity testing and on the quit date will be measured. This novel approach of integrating a human laboratory cue reactivity paradigm directly with a treatment outcome study will allow for evaluation of the predictive value of the human laboratory paradigm. In addition to randomization to the follicular or luteal phase for target quit date, subjects will be randomized to receive one of two active pharmacotherapeutic interventions for smoking cessation: varenicline vs. transdermal nicotine patch (TNP) in a randomized, double-blind, double dummy design. While TNP has demonstrated modest efficacy in improving smoking cessation outcomes, there is some evidence that its efficacy may be more robust in men as compared to women. This project will investigate several novel areas and provide important information about a) optimal timing for smoking quit dates in women, b) the relationship between response in cue reactivity paradigms and smoking cessation and c) comparison of a new pharmacotherapeutic agent to TNP in women.