title: Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice.
abstract: BACKGROUND
  Although a large body of evidence suggests a role for the opioid system in alcoholism, the precise role of mu-, delta-, kappa-, and ORL1-opioid receptors and the physiological significance of their natural genetic variation have not been identified. The method of targeted gene disruption by homologous recombination has been used to knock out (KO) genes coding for opioid receptors, and study their effects on alcohol self-administration. Here we examined the effects of targeted disruption of kappa-opioid receptor (KOR) on oral alcohol self-administration and other behaviors.
  
  
  METHODS
  Oral alcohol, saccharin and quinine self-administration was assessed in a two-bottle choice paradigm using escalating concentrations of alcohol, or tastant solutions. In preference tests 12% alcohol, 0.033% and 0.066% saccharin, and 0.03 mM and 0.1 mM quinine solutions were used. Open-field activity was determined in an arena equipped with a computer-controlled activity-detection system. Subjects were tested for three consecutive days. Locomotor activity was assessed on days 1 and 2 (after saline injection, i.p.) and on day 3 (after alcohol injection, i.p.). Alcohol-induced locomotor activity was determined as the difference in activity between day 3 and day 2.
  
  
  RESULTS
  Male KOR KO mice in preference tests with 12% alcohol consumed about half as much alcohol as wild-type (WT) or heterozygous (HET) mice, showed lower preference for saccharin (0.033% and 0.066%) and higher preference to quinine (0.1 mM) than WT mice. Female KOR KO mice showed similar reduction in alcohol consumption in comparison to WT and HET mice. Partial deletion of KOR in HET mice did not change alcohol consumption in comparison to WT mice. In all genotype-groups females drank significantly more alcohol than males. MANOVA of locomotor activity among KO, WT, and HET mice indicated that strain and sex effects were not significant for alcohol-induced activation (p > 0.05), while strain x sex interaction effects on alcohol-induced activation could be detected (F(1,55) = 6.07, p < 0.05).
  
  
  CONCLUSIONS
  Our results indicating decreased alcohol consumption, lower saccharin preference, and higher quinine preference in KOR KO mice are in line with previous observations of opioid involvement in maintenance of food intake and raise the possibility that the deficient dynorphin/KOR system affects orosensory reward through central mechanisms which reduce alcohol intake and disrupt tastant responses, either as direct effects of absence of kappa-opioid receptors, or as effects of indirect developmental compensatory changes.
authors.affiliation: Laboratory of Neurobehavioral GeneticsNathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, USA. kkovacs@nki.rfmh.org
authors.forename: Krisztina M
authors.initials: KM
authors.lastname: Kovacs
authors.forename: Istvan
authors.initials: I
authors.lastname: Szakall
authors.forename: Danielle
authors.initials: D
authors.lastname: O'Brien
authors.forename: Ray
authors.initials: R
authors.lastname: Wang
authors.forename: K Yaragudri
authors.initials: KY
authors.lastname: Vinod
authors.forename: Mariko
authors.initials: M
authors.lastname: Saito
authors.forename: Frederic
authors.initials: F
authors.lastname: Simonin
authors.forename: Brigitte L
authors.initials: BL
authors.lastname: Kieffer
authors.forename: Csaba
authors.initials: C
authors.lastname: Vadasz
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics* / Q000523:psychology; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004327:Drinking Behavior / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D011803:Quinine; D017473:Receptors, Opioid, kappa / Q000235:genetics*; D012439:Saccharin; D013649:Taste / Q000235:genetics
chemical_list: D002492:Central Nervous System Depressants; D017473:Receptors, Opioid, kappa; D000431:Ethanol; D011803:Quinine; D012439:Saccharin