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Biol Psychiatry. 2014 May 15;75(10):774-82. doi: 10.1016/j.biopsych.2013.03.014. Epub 2013 Apr 21.

The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors.

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Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington.
Veterinary, Comparative Anatomy, Pharmacology and Physiology Department, Washington State University, Pullman, Washington.
Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington.
Neuroscience Drug Discovery, H. Lundbeck A/S, Copenhagen, Denmark.
Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington. Electronic address:



The dynorphin (DYN)/kappa-opioid receptor (KOR) system undergoes neuroadaptations following chronic alcohol exposure that promote excessive operant self-administration and negative affective-like states; however, the exact mechanisms are unknown. The present studies tested the hypothesis that an upregulated DYN/KOR system mediates excessive alcohol self-administration that occurs during withdrawal in alcohol-dependent rats by assessing DYN A peptide expression and KOR function, in combination with site-specific pharmacologic manipulations.


Male Wistar rats were trained to self-administer alcohol using operant behavioral strategies and subjected to intermittent alcohol vapor or air exposure. Changes in self-administration were assessed by pharmacologic challenges during acute withdrawal. In addition, 22-kHz ultrasonic vocalizations were utilized to measure negative affective-like states. Immunohistochemical techniques assessed DYN A peptide expression and [(35)S]GTPγS coupling assays were performed to assess KOR function.


Alcohol-dependent rats displayed increased alcohol self-administration, negative affective-like behavior, DYN A-like immunoreactivity, and KOR signaling in the amygdala compared with nondependent control rats. Site-specific infusions of a KOR antagonist selectively attenuated self-administration in dependent rats, whereas a mu-opioid receptor/delta-opioid receptor antagonist cocktail selectively reduced self-administration in nondependent rats. A mu-opioid receptor antagonist/partial KOR agonist attenuated self-administration in both cohorts.


Increased DYN A and increased KOR signaling could set the stage for a one-two punch during withdrawal that drives excessive alcohol consumption in alcohol dependence. Importantly, intracentral nucleus of the amygdala pharmacologic challenges functionally confirmed a DYN/KOR system involvement in the escalated alcohol self-administration. Together, the DYN/KOR system is heavily dysregulated in alcohol dependence and contributes to the excessive alcohol consumption during withdrawal.


Alcohol; amygdala; dependence; dynorphin; kappa opioid receptor; self-administration; withdrawal

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