title: The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors.
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.
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Kissler
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sirohi
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Reis
authors.affiliation: Veterinary, Comparative Anatomy, Pharmacology and Physiology Department, Washington State University, Pullman, Washington.
authors.forename: Heiko T
authors.initials: HT
authors.lastname: Jansen
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Quock
authors.affiliation: Neuroscience Drug Discovery, H. Lundbeck A/S, Copenhagen, Denmark.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Smith
authors.affiliation: Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington. Electronic address: brendan.walker@wsu.edu.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Walker
mesh_terms: D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000008:administration & dosage*; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; C030738:dynorphin receptor; D000431:Ethanol
keywords: Alcohol; amygdala; dependence; dynorphin; kappa opioid receptor; self-administration; withdrawal