Neutral endopeptidase and alcohol consumption, experiments in neutral endopeptidase-deficient mice

Alcohol consumption was investigated in mice which were rendered deficient in the peptide-degrading enzyme neutral endopeptidase (EC 3.4.24.11) (NEP - / -) by gene targeting and compared to alcohol consumption in corresponding wild type mice (NEP + / +). Mice were offered a free choice to drink tap water or 10% alcohol. The NEP - / - mice consumed significantly more alcohol (approximate to 42%) than the NEP + / + mice, whereas no significant differences were observed in the total fluid consumption. The daily food consumption of alcohol naive NEP - / - animals was elevated (approximate to 29%). Furthermore, the activities of peptidases closely related to neutral endopeptidase were analysed ex vivo in several brain regions from NEP - / - and NEP + / + mice not treated with alcohol. There was no obvious compensation for the total loss of neutral endopeptidase by the functionally related peptidases angiotensin-converting enzyme and aminopeptidase N. In vitro, the degradation of exogenously applied [Leu(5)]enkephalin was not reduced in membrane preparations of those brain regions assayed in NEP - / - mice. A small reduction in [Leu(5)]enkephalin degradation was detected in striatal membrane preparations of NEP - / - mice, if aminopeptidase N was additionally blocked by bestatin or amastatin. (C) 2000 Elsevier Science B.V. All rights reserved.