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The Journal of Neuroscience, January 9, 2008, 28(2):407-414; doi:10.1523/JNEUROSCI.4458-07.2008
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Behavioral/Systems/Cognitive
The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin-Opioid System
Benjamin B. Land,1,2 * Michael R. Bruchas,1 * Julia C. Lemos,2 Mei Xu,1 Erica J. Melief,1 andCharles Chavkin1,2 1Department of Pharmacology and 2Graduate Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195-7280
Correspondence should be addressed to Dr. Charles Chavkin, Department of Pharmacology, University of Washington School of Medicine, Box 357280, Seattle, WA 98195-7280. Email: cchavkin{at}u.washington.edu
Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a
-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. Injection of corticotropin-releasing factor (CRF) or urocortin III, key mediators of the stress response, produced place aversion that was also blocked by dynorphin gene deletion or KOR antagonism. CRF-induced place aversion was blocked by the CRF2 receptor antagonist antisauvigine-30, but not by the CRF1 receptor antagonist antalarmin. In contrast, place aversion induced by the KOR agonist U50,488 was not blocked by antisauvigine-30. These results suggest that the aversive effects of stress were mediated by CRF2 receptor stimulation of dynorphin release and subsequent KOR activation. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria, and emphasizes
Key words: dynorphin; aversion; stress-induced aversion; drug addiction;
Received Sept. 28, 2007; revised Nov. 13, 2007; accepted Nov. 19, 2007.
Correspondence should be addressed to Dr. Charles Chavkin, Department of Pharmacology, University of Washington School of Medicine, Box 357280, Seattle, WA 98195-7280. Email: cchavkin{at}u.washington.edu
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