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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.

Author information

1
Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington.
2
Veterinary, Comparative Anatomy, Pharmacology and Physiology Department, Washington State University, Pullman, Washington.
3
Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington.
4
Neuroscience Drug Discovery, H. Lundbeck A/S, Copenhagen, Denmark.
5
Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington. Electronic address: brendan.walker@wsu.edu.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

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

PMID:
23611261
PMCID:
PMC3749293
DOI:
10.1016/j.biopsych.2013.03.014
[Indexed for MEDLINE]
Free PMC Article

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