Core Research Component 1:  
Oxytocin and Cocaine Dependence

Co-Principal Investigators: 
Kathleen Brady and Aimee McRae-Clark

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 will examine 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 propose an evaluation of the impact of OT on the endocrine, physiological and subjective response to a laboratory stressor in cocaine-dependent men and women. In addition, fMRI will be 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. The impact of estrogen and progesterone on stress and cue reactivity will also be 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.

The studies proposed in Project I fit well with Project II’s studies of sex differences in the impact of neuropeptides, including OT, on cocaine taking and reinstatement in rats. They also complement the study proposed by Dr. Aston Jones exploring sex differences in the neural circuitry of stress systems, including OT, in drug seeking during early abstinence in nonhumans. Thus, these studies may help define gender-specific pharmacological targets to promote drug abstinence and prevent relapse. Finally, Project I uses many of the same assessments and experimental paradigms as those in Project IV allowing for comparative and complementary analysis across projects to elucidate similarities and differences in biologic and environmental influences in the relationship between stress and nicotine/cocaine dependence.

Core Research Component 2: 
Sex Differences in Orexin and Oxytocin Mediation of Cocaine-seeking

Principal Investigator: 
Ronald See

Over the past two funding periods, 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 will examine 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, Dr. Gary Aston-Jones will join the SCOR as a core project PI. Dr. Aston-Jones has conducted ground-breaking research on the function of the locus coeruleus and hypothalamic neuropeptides in a number of disease states, including addictions. The investigators will 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.

This project relates closely to the other projects proposed in this application. NE is a major input to OT/vasopressin neurons, and there are strong CRF-OT and NE-orexin interactions/projections as well. Therefore, findings from Projects II and III will inform each other about connections among these systems involved in gender-specific responses to abused drugs. For example, Project III will inform Project II about NE or CRF upstream systems that may modulate the OT response during stress, and conversely Project II will inform this project about the role of OT in effects of NE and CRF on drug-seeking. This project will also provide information about sex differences in neurotransmitters involved in the stress response that may be used in targeting specific areas (e.g., PFC, a major target of LC) during the fMRI sessions proposed in Project I.

Co-PIs: 
Michael Saladin and Kevin Gray

Paralleling some of the methodological features of Project I, Project IV will examine 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 proposed study will track 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, will join 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).

The focus of Project IV on the connection between gender, neuropeptides, stress and smoking provides strategic links to the other Center projects. Both clinical projects (I and IV) will use a common assessment battery, hormonal measurement and human laboratory paradigms/procedures, including OT administration and the Trier Social Stressor Task allowing for comparative and complementary analysis across projects. The assessment of ad libitum smoking behavior in the period after OT/placebo administration provides a tie between the studies in Project III focused on the neural circuitry involved in initiation of use in early abstinence.

Updated 07/2012