Core Research Component 1: Oxytocin and Cocaine Dependence
Co-Principal Investigators: Kathleen Brady and Aimee McRae-Clark
Co-Investigators: Jane Joseph and Megan Moran-Santa Maria
This project is a direct extension of previous SCOR work conducted by this investigative team. Work from our previous and on-going studies suggest that modulation of the stress response might be a particularly important therapeutic target for women. To extend this work, we are currently examining the potential role of oxytocin (OT), a hypothalamic neuropeptide shown to mediate behavioral responding to stress and play a role in the neuroadaptations that occur as a consequence of long-term drug use. Thus, OT may have a therapeutic role in ameliorating the negative affect commonly observed prior to relapse in cocaine-dependent individuals. Further, as estrogen appears to enhance OT’s effects, females may have an enhanced response to OT. We are evaluating the impact of OT on the endocrine, physiological and subjective response to a laboratory stressor in cocaine-dependent men and women. In addition, fMRI is used to assess gender differences in the neural response to OT and to evaluate the impact of OT on functional brain activity in limbic and striatal nuclei during a cue-reactivity task, and the impact of estrogen and progesterone on stress and cue reactivity is also measured. In the follow-up period, gender differences in the impact of stress and cocaine cues on the initiation of cocaine use after a period of abstinence in the natural environment will be explored.
Core Research Component 2: Sex Differences in Orexin and Oxytocin Mediation of Cocaine-seeking
Principal Investigator: Carmela Reichel
Co-Investigators: Luyi Zhou
Over the past decade, this investigative team has extensively characterized sex differences in reinstatement to cocaine-seeking in rats produced by various triggers of relapse (stress, cues, and drugs) and estrous-cycle dependent changes in females. These studies support the general hypothesis that there are sex differences in factors associated with cocaine seeking and females demonstrate greater sensitivity to stress-induced reinstatement. Building on these findings, this project examines key neuropeptide substrates that may underlie sex and estrous cycle dependent differences in reinstatement. In particular, the studies focus on identifying the mechanisms for sex and estrous cycle-dependent differences in OT and orexin-mediated cocaine taking and reinstatement. Because of the common focus on sex/gender differences and relapse, including the relationship of ovarian hormones to drug seeking, this project integrates well with the clinical SCOR projects. This project also integrates with Project III, which examines another hypothalamic stress-associated system (CRF input to LC) and the relationship to OT in cocaine-seeking in males and female rats. The data from these projects should provide a more comprehensive picture of sex differences in the neural circuitry and hypothalamic neuropeptides involved in stress-induced relapse.
Core Research Component 3: Stress Circuits and Sex Differences in Drug Seeking
Principal Investigator: Gary Aston-Jones
Numerous studies show that the brain norepinephrine (NE) and CRF systems are important in stress responses. Recent findings reveal sex differences in these brain systems that seem likely to be involved in the sex/gender differences in stress-associated cocaine relapse that has been elucidated by MUSC SCOR investigators. In animal models, LC-NE neurons in females are more responsive to stressors and to CRF1 receptor activation than in males, independent of estrous cycle. In addition, oxytocin (OT) neurons are involved in reward processes, perhaps via interactions with NE and CRF, and may play a role in drug craving. To gain a clearer understanding of how CRF, NE and OT might be involved in elevated cocaine sensitivity and stress-associated drug seeking in females, the investigators use dual-label immunohistochemistry and CRF and NE receptor antagonists in a reinstatement paradigm to identify a CRF-NE circuit involved in cocaine seeking during early abstinence. Preliminary results show gender differences in this behavioral measure and sensitivity to both NE and CRF antagonist pretreatments.
Core Research Component 4: Gender, Sex Hormones and Stress-related Smoking
Co-Principal Investigators: Michael Saladin and Kevin Gray
Co-Investigators: Steve Tiffany
Paralleling some of the methodological features of Project I, Project IV examines the effects of OT on stress-induced changes in the smoking behavior of nicotine-dependent men and women. In addition, a critical progression from research to date is the translation of findings from laboratory procedures into the “real world” environment of smokers. Specifically, the study tracks female and male smokers over a two-week period with frequent assessment of reproductive hormone levels, reactivity to cues, levels of subjective emotion/stress, and smoking behavior across natural and laboratory environments using Cue Reactivity Ecological Momentary Assessment (or CREMA) software. Dr. Steve Tiffany, an internationally recognized researcher in addictions, has joined this investigative team. Dr. Tiffany has published extensively on the relationship between craving, stress and negative emotion. His most recent work has examined smoking cue reactivity in the natural environment of smokers using CREMA (Gass et al., 2011; Warthen and Tiffany, 2009).