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Plasticity and impact of the central renin–angiotensin system during development of ethanol dependence

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Abstract

Pharmacological and genetic interference with the renin–angiotensin system (RAS) seems to alter voluntary ethanol consumption. However, understanding the influence of the RAS on ethanol dependence and its treatment requires modeling the neuroadaptations that occur with prolonged exposure to ethanol. Increased ethanol consumption was induced in rats through repeated cycles of intoxication and withdrawal. Expression of angiotensinogen, angiotensin-converting enzyme, and the angiotensin II receptor, AT1a, was examined by quantitative reverse transcription polymerase chain reaction. Increased ethanol consumption after a history of dependence was associated with increased angiotensinogen expression in medial prefrontal cortex but not in nucleus accumbens or amygdala. Increased angiotensinogen expression also demonstrates that the astroglia is an integral part of the plasticity underlying the development of dependence. The effects of low central RAS activity on increased ethanol consumption were investigated using either spirapril, a blood–brain barrier-penetrating inhibitor of angiotensin-converting enzyme, or transgenic rats (TGR(ASrAOGEN)680) with reduced central angiotensinogen expression. Spirapril reduced ethanol intake in dependent rats compared to controls. After induction of dependence, TGR(ASrAOGEN)680 rats had increased ethanol consumption but to a lesser degree than Wistar rats with the same history of dependence. These data suggest that the central RAS is sensitized in its modulatory control of ethanol consumption in the dependent state, but pharmacological or genetic blockade of the system appears to be insufficient to halt the progression of dependence.

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Acknowledgment

Supported by EC through TARGALC grant to M.H. (QLG3-CT-2002-01048) and by DFG through a grant to M.B. (BA1374/11-1). Spirapril was provided by H. Jainta (Arzneimittelwerk, Dresden, Germany).

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Authors and Affiliations

  1. Laboratory of Clinical and Translational Studies, NIAAA, NIH, Bldg 10, CRC, E1-5330, 10 Center Dr, Bethesda, MD, 20892-1108, USA

    W. H. Sommer, J. Lidström & M. Heilig

  2. Department of Pharmacology, University of Bologna, Bologna, Italy

    R. Rimondini

  3. Department of Anatomy, University of Jena, Jena, Germany

    M. Marquitz

  4. Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany

    W-E Siems

  5. Max-Delbrück-Center for Molecular Medicine, Berlin-Buch, Germany

    M. Bader

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  1. W. H. Sommer
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  4. J. Lidström
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  5. W-E Siems
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  6. M. Bader
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  7. M. Heilig
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Correspondence to W. H. Sommer.

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Sommer, W.H., Rimondini, R., Marquitz, M. et al. Plasticity and impact of the central renin–angiotensin system during development of ethanol dependence. J Mol Med 85, 1089–1097 (2007). https://doi.org/10.1007/s00109-007-0255-5

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  • DOI: https://doi.org/10.1007/s00109-007-0255-5

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