Component 1:  "Sex and Estrous Cycle-Dependent Differences in Drug-Seeking Behavior"

Principal Investigator:  Ronald See, Ph.D.

This project is designed to examine sex differences and hormonal regulation in an animal model of relapse to cocaine- and nicotine-seeking behavior.  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.  Studies have found that selective pharmacological agents will produce reliable stress-induced reinstatement, in particular the α2-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 is 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 (α2-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.

Component 2:  "Stress-Induced Craving: The Impact of Sex and Ovarian Hormones"

Principal Investigator:  Kathleen Brady, M.D., Ph.D.

This project explores a novel human laboratory approach to the study of stress-induced craving and 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.

Component 3:  "Menstrual Cycle Effects on Smoking Cessation and Cue Reactivity"

Principal Investigators:  Kevin Gray, M.D. and Michael Saladin, Ph.D.

The primary specific aims of this component are to (1) examine the impact of the timing of quit date within the menstrual cycle (based on ovarian hormone levels) on smoking cessation treatment success, and (2) examine the relationship between subjective (e.g., craving) and physiological (e.g., heart rate, skin conductance) responses to smoking cues in a human laboratory paradigm and smoking cessation treatment outcome in nicotine-dependent women.  We are also exploring differential treatment outcomes in women treated with varenicline vs. transdermal nicotine patch.  No substantive changes have been made to the specific aims from the original application.  Nicotine dependence is a major public health concern, with more than 25% of the adult population being current smokers. Among individuals with nicotine dependence, craving is an important component of the symptoms experienced during smoking cessation and is considered to be an important factor in relapse to smoking.  The present proposal builds directly upon the results of our previous study and explores the effects of ovarian hormone levels at the time of quit attempt on treatment success. By tying together a human laboratory cue-reactivity paradigm (developed during the initial funding period) with a treatment outcome study, we will be able to assess whether pre-treatment responses to smoking cues predict measures of treatment outcome. The results of the current study may yield important practical information that will aid women in setting a quit date in the ovarian hormonal milieu that is most associated with successful quitting, thereby enhancing treatment outcome.