Pharmacological and genetic interference with the renin angiotensin system (RAS) seems to alter voluntary ethanol consumption. Furthermore, increased gene expression of angiotensinogen (Agt) was consistently found in the brain of mouse (HAP) and rat (P, AA) lines selectively bred for high ethanol preference compared to their respective controls. Agt appears to be a node in gene-gene interactions regulating ethanol intake. 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 RT-PCR. Increased ethanol consumption following 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.

PLASTICITY AND IMPACT OF THE CENTRAL RENIN-ANGIOTENSIN SYSTEM DURING DEVELOPMENT OF ETHANOL DEPENDENCE

RIMONDINI GIORGINI, ROBERTO;
2008

Abstract

Pharmacological and genetic interference with the renin angiotensin system (RAS) seems to alter voluntary ethanol consumption. Furthermore, increased gene expression of angiotensinogen (Agt) was consistently found in the brain of mouse (HAP) and rat (P, AA) lines selectively bred for high ethanol preference compared to their respective controls. Agt appears to be a node in gene-gene interactions regulating ethanol intake. 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 RT-PCR. Increased ethanol consumption following 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.
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
82a
82a
W. H. Sommer; J. Lidstrom; R. Rimondini; M. Bader; M. Heilig
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/112476
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