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Journals The FASEB Journal Volume 19 Issue 11

Central angiotensin II controls alcohol consumption via its AT1 receptor Björn Maul, Winfried Krause, Kristin Pankow, Matthias Becker, Florian Gembardt * ,# , Natalia Alenina ‡ , Thomas Walther * ,# , Michael Bader ‡ and Wolf-Eberhard Siems 1 Institute of Molecular Pharmacology, Berlin, Germany; * Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands; # Department of Cardiology, Charité Berlin, Campus Benjamin Franklin, Berlin, Germany; and ‡ Max Delbrück Center for Molecular Medicine, Berlin, Germany 1 Correspondence: FMP (Forschungsinstitut für Molekulare Pharmakologie), Robert-Rössle-Strasse 10, D-13125 Berlin, Germany. E-mail: siems@fmp-berlin.de Pharmacological and genetic manipulations of the renin-angiotensin system (RAS) have been found to alter the voluntary consumption of alcohol. Here we characterize the role of central angiotensin II (Ang II) in alcohol intake first by using transgenic rats that express an antisense RNA against angiotensinogen and consequently have reduced Ang II levels exclusively in the central nervous system TGR(ASrAOGEN)680. These rats consumed markedly less alcohol in comparison to their wild-type controls. Second, Spirapril, an inhibitor of the angiotensin-converting enzyme (ACE), which passes the blood-brain barrier, did not influence the alcohol consumption in the TGR(ASrAOGEN)680, but it significantly reduced alcohol intake in wild-type rats. Studies in knockout mice indicated that the central effect of Ang II on alcohol consumption is mediated by the angiotensin receptor AT1 whereas the AT2 receptor and the bradykinin B2 receptor are not involved. Furthermore, the dopamine concentration in the ventral tegmental area (VTA) is markedly reduced in rats with low central Ang II, strengthening our hypothesis of a role of dopaminergic transmission in Ang II-controlled alcohol preference. Our results indicate that a distinct drug-mediated control of the central RAS could be a promising therapy for alcohol disease.— Maul, B., Krause, W., Pankow, K., Becker, M., Gembardt, F., Alenina N., Walther, T., Bader, M., Siems, W.-E. Central angiotensin II controls alcohol consumption via its AT1 receptor. Key Words: angiotensin • dopamine • alcohol • knockout mice • transgenic rats

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