title: Genetic deficiency in neprilysin or its pharmacological inhibition initiate excessive stress-induced alcohol consumption in mice.
abstract: Both acquired and inherited genetic factors contribute to excessive alcohol consumption and the corresponding development of addiction. Here we show that the genetic deficiency in neprilysin [NEP] did not change the kinetics of alcohol degradation but led to an increase in alcohol intake in mice in a 2-bottle-free-choice paradigm after one single stress stimulus (intruder). A repetition of such stress led to an irreversible elevated alcohol consumption. This phenomenon could be also observed in wild-type mice receiving an orally active NEP inhibitor. We therefore elucidated the stress behavior in NEP-deficient mice. In an Elevated Plus Maze, NEP knockouts crossed more often the area between the arms, implicating a significant stronger stress response. Furthermore, such animals showed a decreased locomotor activity under intense light in a locomotor activity test, identifying such mice to be more responsive in aversive situations than their wild-type controls. Since the reduction in NEP activity itself does not lead to significant signs of an altered alcohol preference in mice but requires an environmental stimulus, our findings build a bridge between stress components and genetic factors in the development of alcoholism. Therefore, targeting NEP activity might be a very attractive approach for the treatment of alcohol abuse in a society with increasing social and financial stress.
authors.affiliation: Department for Biochemical Neurobiology, Leibnizinstitut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Maul
authors.forename: Matthias
authors.initials: M
authors.lastname: Becker
authors.forename: Florian
authors.initials: F
authors.lastname: Gembardt
authors.forename: Axel
authors.initials: A
authors.lastname: Becker
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Wolf-Eberhard
authors.initials: WE
authors.lastname: Siems
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
mesh_terms: D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D000437:Alcoholism / Q000201:enzymology / Q000235:genetics*; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D000431:Ethanol / Q000097:blood; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007189:Indans / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D011422:Propionates / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D007189:Indans; D011422:Propionates; D011480:Protease Inhibitors; D000431:Ethanol; C062766:candoxatril; D015260:Neprilysin