Viral-vector-induced steroidogenesis in the VTA increases 3 alpha,5 alpha-THP and reduces long-term operant ethanol self-administration (Abstract/Poster in atti di convegno)

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  • Viral-vector-induced steroidogenesis in the VTA increases 3 alpha,5 alpha-THP and reduces long-term operant ethanol self-administration (Abstract/Poster in atti di convegno) (literal)
Anno
  • 2014-01-01T00:00:00+01:00 (literal)
Alternative label
  • Morrow, A. Leslie; Cook, Jason B.; Werner, David F.; Maldonado-Devincci, Antoniette M.; Leonard, Maggie N.; Fisher, Kristen R.; O'Buckley, Todd K.; Porcu, Patrizia; McCown, Thomas J.; Hodge, Clyde W.; Besheer, Joyce (2014)
    Viral-vector-induced steroidogenesis in the VTA increases 3 alpha,5 alpha-THP and reduces long-term operant ethanol self-administration
    in Alcoholism and Stress: A Framework for Future Treatment Strategies, Volterra, Italy, 6-9 May 2014
    (literal)
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  • Morrow, A. Leslie; Cook, Jason B.; Werner, David F.; Maldonado-Devincci, Antoniette M.; Leonard, Maggie N.; Fisher, Kristen R.; O'Buckley, Todd K.; Porcu, Patrizia; McCown, Thomas J.; Hodge, Clyde W.; Besheer, Joyce (literal)
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  • 159 (literal)
Pagina fine
  • 160 (literal)
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  • 48 (literal)
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  • 48 (literal)
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  • 2 (literal)
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  • 2 (literal)
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  • ISI Web of Science (WOS) (literal)
  • Abstract (literal)
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  • UNC Sch Med, Chapel Hill, NC, USA (literal)
Titolo
  • Viral-vector-induced steroidogenesis in the VTA increases 3 alpha,5 alpha-THP and reduces long-term operant ethanol self-administration (literal)
Abstract
  • The GABAergic neuroactive steroid (3alpha,5alpha)-3-hydroxypregnan-20-one (3alpha,5alpha-THP) alters ethanol consumption with bi-directional actions. To optimize the therapeutic potential for neuroactive steroids, we employed vector-mediated gene delivery to alter neurosteroids at specific brain sites. We developed a recombinant adeno-associated-viral-vector (rAAV) to drive neurosteroidogenesis by delivery of cytochrome P450 side chain cleavage (P450scc), the rate-limiting enzymatic reaction in steroidogenesis. Following vector characterization, we studied the effect of rAAV2-P450scc vector delivery to VTA and NAc on ethanol reinforcement and consumption in alcohol-preferring (P) rats. rAAV2-P450scc or control green fluorescent protein expressing vector (rAAV2-GFP) was injected bilaterally into the VTA or NAc of alcohol preferring (P) rats previously trained to self-administer ethanol. rAAV2-P450scc vector delivery to the VTA specifically reduced ethanol responding by 20% (two-way ANOVA, p < 0.005) and ethanol intake by 14% (two-way ANOVA, p < 0.01) compared to control rats over 3 weeks. In contrast, P450scc overexpression in the NAc did not alter ethanol self-administration. General locomotor activity and thigmotaxis were not changed. P450scc overexpression in the VTA produced a 36% increase in 3alpha,5alpha-THP positive cells in the VTA, however, transduction of NAc did not increase local 3alpha,5alpha-THP immunoreactivity. VTA neurons were co-labeled with 3alpha,5alpha-THP and tyrosine hydroxylase, or solely labeled by 3alpha,5alpha-THP. Thus, P450scc gene delivery increased 3alpha,5alpha-THP positive cells in the VTA, causing a persistent reduction of ethanol reinforcement and consumption. rAAV2-P450scc is a useful tool for studying the role of neuroactive steroids in ethanol reinforcement and consumption, and may provide new therapeutic strategies for treatment of alcoholism. Supported by NIAAA and the Bowles Center for Alcohol Studies. (literal)
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