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

• Published in: European journal of pharmacology 2000-06, Vol.397 (2), p.327-334
• Main Authors: Siems, Wolf-Eberhard, Maul, Bjoern, Krause, Winfried, Gerard, Craig, Hauser, Kurt F, Hersh, Louis B, Fischer, Hanspeter S, Zernig, Gerald, Saria, Alois
• Format: Article
• Language: English
• Subjects: Alcohol consumption; Alcohol Drinking; Alcoholism and acute alcohol poisoning; Angiotensin-converting enzyme; Animals; Auditory Cortex - metabolism; Biological and medical sciences; Brain - enzymology; CD13 Antigens - metabolism; Cerebral Cortex - metabolism; Corpus Striatum - metabolism; Enkephalin; Enkephalin, Leucine - metabolism; Enkephalin-degrading peptidases; Enkephalinase; Genotype; Hippocampus - metabolism; Knockout mouse; Male; Medical sciences; Membranes - metabolism; Mesencephalon - metabolism; Mice; Mice, Knockout; Neprilysin - genetics; Neprilysin - metabolism; Neutral endopeptidase; Olfactory Bulb - metabolism; Opioid; Peptidyl-Dipeptidase A - metabolism; Thalamus - metabolism; Toxicology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(00)00222-3

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 (≈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 (≈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.