This R03 proposal was written in response to PA-11-049, "Women and Sex/Gender Differences in Drug and Alcohol Abuse/Dependence". Growing evidence shows that drug-dependent women express greater negative affect than men (1, 2, 3, 4) and negative emotional states such as stress and depression are more likely to trigger craving and relapse in women (5, 6). Research in males has shown that aversive and depressive-like states are mediated, in part, by the neuropeptide dynorphin, an endogenous ligand that acts at kappa opioid receptors (7). Chronic exposure to drugs of abuse promotes the synthesis and release of dynorphin that is coincident with the emergence of depressive-like effects (8, 9, 10). The purpose of this proposal is to examine sex differences in the regulation and role of kappa-opioid receptors in mediating negative affective states in rats. Understanding the biological basis of these differences is crucial to developing better treatments for both men and women. Chartoff and colleagues have begun to examine the role of kappa-opioid receptors in males and females using intracranial self-stimulation (ICSS), an operant conditioning paradigm that is sensitive to increases or decreases in reward function "in real time". Kappa- opioid receptor agonists increase stimulation thresholds in ICSS, which is indicative of a decrease in reward function (anhedonia). Preliminary results show that females are less sensitive to the threshold-increasing effects of the kappa-opioid receptor agonist U50,488. Given that the majority of sex differences have been linked to actions of circulating gonadal steroid hormones, this proposal uses two complementary approaches to test the role of gonadal hormones in kappa-opioid receptor function. First, the effects of U50,488 on ICSS thresholds will be determined in gonadectomized rats. If gonadectomy abolishes the sex difference in the depressive-like effects of KOR activation, then it is likely that activational effects of gonadal steroid hormones are required. Although a fairly basic question, it is fundamental to the understanding of mood dysfunction in drug addiction. Second, the role of sex and gonadal steroid hormones on kappa-opioid receptor mRNA levels and U50,488-induced coupling to downstream effectors will be determined within brain regions that regulate reward function. If receptor levels or coupling are modulated by sex or sex hormones, then it is likely that differences in the behavioral effects of kappa-opioid receptor activation are due, in part, to receptor pharmacodynamics. Data from these studies will lead to a better understanding of how kappa-opioid receptors regulate affective states in males and females and will form a foundation for future research on sex differences in the role of kappa-opioid receptors in drug addiction.

Public Health Relevance

Women drug addicts express greater negative emotional states then men, and understanding the biological basis of these differences is crucial to developing better treatments for both men and women. It has been shown in males that chronic exposure to drugs of abuse elicits neuroadaptations in stress and reward pathways, including enhanced synthesis and release of dynorphin!an endogenous ligand at kappa opioid receptors that is coincident with the emergence of depressive-like effects. The goal of the proposed studies is to explore potential sex differences in the regulation and role of kappa-opioid receptors as they relate to depressive-like states.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
1R03DA033526-01A1
Application #
8444087
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
2013-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$79,000
Indirect Cost
$29,000
Name
Mclean Hospital
Department
Type
DUNS #
046514535
City
Belmont
State
MA
Country
United States
Zip Code
02478
Russell, Shayla E; Rachlin, Anna B; Smith, Karen L et al. (2014) Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats. Biol Psychiatry 76:213-22