Pharmacological activation of kappa opioid receptors (KOR) in humans elicits reports of dysphoria, and KOR activation by agonists or by stress-evoked dynorphin release in rodents produces aversion. These dysphoric/aversive effects of KOR activation have been shown to increase the rewarding effects of cocaine, increase drug self-administration, and reinstate extinguished drug seeking behaviors. The cellular and molecular mechanisms responsible for KOR-dependent aversion and potentiation of cocaine reward are not fully understood, but a better understanding may suggest new therapeutic approaches to the treatment and prevention of stress-related diseases including some forms of drug addiction. Evidence strongly supports a role for KOR-dependent inhibition of dopamine (DA) release in the nucleus accumbens (NAc) and KOR-induced activation of p38 mitogen-activated protein kinase (MAPK). We propose to understand how KOR activation and KOR-induced activation of p38 MAPK, either by stress-induced dynorphin release in the ventral tegmental area (VTA) and NAc or by systemic administration of a selective KOR agonist, results in potentiation of the rewarding effects of cocaine. To accomplish these aims we propose 1) to compare the signal transduction pathways underlying KOR-induced potentiation of cocaine-conditioned place preference (cocaine-CPP) to the effects of KOR activation and subsequent administration of cocaine on stimulated DA release in the NAc using fast-scan cyclic voltammetry (FSCV) and 2) to measure KOR-induced potentiation of cocaine-CPP and KOR- mediated interactions with cocaine-induced alterations of DA release using FSCV in animals in which functional KOR activity has been selectively restored to the VTA of KOR knockout (KO) animals.

Public Health Relevance

Although the stress response is generally protective, repeated and uncontrollable stress exposure can increase the risks of mood disorders and drug addiction. The mechanisms underlying these adverse effects need to be understood before better treatments for stress-related diseases can be developed. Activation of the dynorphin/kappa opioid systems in brain has been shown to encode the dysphoric effects of stress. The proposed studies would test the hypothesis that regulation of dopamine release by activation of KOR and KOR-induced activation of p38 MAPK contributes to the stress-induced potentiation of the rewarding properties of addictive drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA030892-02
Application #
8334559
Study Section
Special Emphasis Panel (ZRG1-F03B-H (20))
Program Officer
Babecki, Beth
Project Start
2011-06-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$35,650
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195