Article

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

University of Bologna, Bolonia, Emilia-Romagna, Italy
Journal of Molecular Medicine (Impact Factor: 4.74). 11/2007; 85(10):1089-97. DOI: 10.1007/s00109-007-0255-5
Source: PubMed

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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Available from: Wolfgang H Sommer, Jun 30, 2015
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    • "In our experience, this is unusual because using the intermittent vapor exposure paradigm we robustly induce post-dependent excessive alcohol drinking in a variety of rat lines, including Wistar, Sprague-Dawley, Fisher, and a genetically modified rat line (Sommer et al., 2007). If the findings in AA and ANA rats do indeed represent innate resistance to developing a post-dependent state, it would be highly interesting to identify involved genetic factors. "
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    ABSTRACT: Much research on experimental animals that is aimed to decipher genetic factors involved in alcoholism has been devoted to either models of innate alcohol-related phenotypes or responses after acute alcohol challenge. Such focus has, however, limitations when it comes to the pathogenetic mechanism underlying alcohol addiction, because the progression into the disorder takes years and genetic as well as environmental factors may exert different influences along this trajectory. Animal models of the neuroadaptations involved in the development of dependence exist, but have been difficult to implement for genetic and genomics analysis. Consequently, currently available data have been difficult to reconcile with the human condition and could be misleading in predicting targets for medication development. This review will illustrate strengths and pitfalls of genomic approaches in rodent models of alcoholism and emphasize the need for convergent lines of evidence to improve the predictive value of such studies. Examples of a convergent research approach include validation studies for Agt, Arrb2, Crhr1, Grin3a, and Npy.
    International Review of Neurobiology 01/2010; 91:129-71. DOI:10.1016/S0074-7742(10)91005-2 · 2.46 Impact Factor
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    • "In our experience, this is unusual because using the intermittent vapor exposure paradigm we robustly induce post-dependent excessive alcohol drinking in a variety of rat lines, including Wistar, Sprague-Dawley, Fisher, and a genetically modified rat line (Sommer et al., 2007). If the findings in AA and ANA rats do indeed represent innate resistance to developing a post-dependent state, it would be highly interesting to identify involved genetic factors. "
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