title: Central angiotensin II controls alcohol consumption via its AT1 receptor.
abstract: 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.
authors.affiliation: Institute of Molecular Pharmacology, Berlin, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Maul
authors.forename: Winfried
authors.initials: W
authors.lastname: Krause
authors.forename: Kristin
authors.initials: K
authors.lastname: Pankow
authors.forename: Matthias
authors.initials: M
authors.lastname: Becker
authors.forename: Florian
authors.initials: F
authors.lastname: Gembardt
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Wolf-Eberhard
authors.initials: WE
authors.lastname: Siems
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000428:Alcohol Drinking; D000804:Angiotensin II / Q000502:physiology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000808:Angiotensinogen / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D001921:Brain / Q000502:physiology*; D004298:Dopamine / Q000032:analysis; D004656:Enalapril / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D044140:Receptor, Angiotensin, Type 1; D015102:3,4-Dihydroxyphenylacetic Acid; D000808:Angiotensinogen; D000804:Angiotensin II; D004656:Enalapril; C052555:spirapril; D004298:Dopamine