Abuse of cocaine (COC) is a major public health issue with an estimated 1.6 million Americans confirming current COC use (SAMHSA, 2010). Despite years of treatment research, no FDA-approved medications are currently available, warranting continued investigation of factors involved in COC abuse for improved medication development. Effective treatments relay on a comprehensive understanding of the mechanisms that mediate the behavioral effects of COC. These mechanisms may differ between women and men, and women in particular may be at risk for vulnerability to COC abuse as indicated by evidence of sex differences in both clinical and preclinical research (O'Brien and Anthony, 2005). The factors that predispose an individual to susceptibility to COC abuse and potential indicators for risk of relapse are active aras of research in the drug abuse field~ therefore it is an alarming trend that much of the research regarding these factors is being conducted solely in male subjects. Therefore, one goal of this proposal is to extend the research that has been completed using socially housed male monkeys to socially housed female monkeys. Behavioral and neurochemical evidence supports the hypothesis that endogenous hormones, specifically those which fluctuate across the menstrual cycle- estrogen and progesterone, interact with receptors known to be involved in drug self-administration (SA) and cognition. Additionally, social status and COC SA have been shown to influence endogenous hormone concentrations. Therefore, this application will use a female nonhuman primate model to investigate how endogenous hormones and cognitive performance is altered as social hierarchies are established and COC SA is initiated. The first part of the study aims to characterize how baseline hormonal profiles affect cognitive performance in each animal and may predispose animals to attain a certain rank once group-housed (future dominant vs future subordinate). Secondly, the proposed study will assess how these variables (hormonal profile and cognitive performance) are altered following socially derived stress as a result of group-housing. Finally, I will elucidate how alteratons to endogenous female hormones influence susceptibility to COC SA in a food-COC choice paradigm. Additionally, this research will assess the behavioral relevance of COC SA on cognition examining the effects it has on cognitive performance. The proposed studies will effectively model the role of chronic stress and hormone/cognitive dysregulation on vulnerability to the reinforcing effects of COC. The studies that have previously attempted to examine these factors individually are inconsistent and limited in that assessing each manipulation individually (i.e. social status, COC SA and cognition) with different paradigms does not encompass the potential synergistic effects that these variables can have in human abusers. These studies will enhance the understanding of these effects to ultimately provide translational insight into novel pharmacotherapeutic treatment strategies.
The research proposed in the NRSA addresses a major concern for public health and women's health by examining the neurobiological role of endogenous hormones in cocaine (COC) abuse. A comprehensive understanding of the behavioral, physiological and neurobiological consequences of social rank and COC SA is critical for understanding the biological processes mediating COC abuse. By using a longitudinal study design to assess the hormonal profile of female monkeys before and after social housing, as well as during COC self-administration (SA) initiation, both during initiation and subsequent chronic COC SA, we will be able to determine relevant alterations that occur throughout the progression of COC abuse and develop hypotheses related to mechanisms that may lead to novel treatment strategies for women COC abusers.
|Kromrey, Sarah A; Czoty, Paul W; Nader, Michael A (2015) Relationship between estradiol and progesterone concentrations and cognitive performance in normally cycling female cynomolgus monkeys. Horm Behav 72:12-9|