Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3alpha,5alpha-THP and reduces long-term operant ethanol self-administration (Comunicazione a convegno)

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  • Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3alpha,5alpha-THP and reduces long-term operant ethanol self-administration (Comunicazione a convegno) (literal)
Anno
  • 2015-01-01T00:00:00+01:00 (literal)
Alternative label
  • Porcu P, Cook JB, Werner DF, Maldonado-Devincci AM, Leonard MN, Fisher KR, O'Buckley TK, McCown TJ, Besheer J, Hodge CW and Morrow AL (2015)
    Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3alpha,5alpha-THP and reduces long-term operant ethanol self-administration
    in 8th International Meeting Steroids and Nervous System, Torino, Italy, 14-19 February 2015
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Porcu P, Cook JB, Werner DF, Maldonado-Devincci AM, Leonard MN, Fisher KR, O'Buckley TK, McCown TJ, Besheer J, Hodge CW and Morrow AL (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url
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  • Neuroscience Institute, National Research Council (CNR), Cagliari, Italy; Bowles Center for Alcohol Studies, Departments of Psychiatry and Pharmacology, Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, USA; Department of Psychology, Binghamton University - State University of New York, Binghamton, USA (literal)
Titolo
  • Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3alpha,5alpha-THP and reduces long-term operant ethanol self-administration (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#curatoriVolume
  • Panzica GC, Gotti S (literal)
Abstract
  • Neuroactive steroids are endogenous neuromodulators that alter neuronal activity and behavior. Systemic administration of neuroactive steroids reduces operant ethanol self-administration in rodents. We hypothesized that this effect of neuroactive steroids may occur at specific mesolimbic brain regions that could be selectively targeted by gene delivery. A recombinant adeno-associated serotype 2 viral vector (rAAV2) expressing the mitochondrial cytochrome P450 side chain cleavage (P450scc) enzyme was used to promote neuroactive steroid synthesis. P450scc converts cholesterol to pregnenolone, which is the rate-limiting enzymatic reaction in neurosteroidogenesis. We first demonstrated that the P450scc expressing vector (rAAV2-P450scc) increased P450scc mRNA in cultured cells and pregnenolone levels in the cell media. Moreover, rAAV2-P450scc vector infusion increased P450scc mRNA and protein levels in vivo. Next, rAAV2-P450scc or control green fluorescent protein (GFP) expressing vector (rAAV2-GFP) were injected bilaterally into the ventral tegmental area (VTA) or nucleus accumbens (NAc) of alcohol preferring (P) rats trained to self-administer ethanol. Operant self-administration sessions resumed following 1 week. P450scc overexpression in the VTA reduced ethanol responding by 20% (p<0.005) and ethanol consumption by 14% (p<0.01) over the 3 week test period. Water intake was not altered. In contrast, P450scc overexpression in the NAc did not alter ethanol self-administration. Locomotor activity was not altered by vector administration in the VTA or NAc. P450scc overexpression in the VTA produced a 36% increase in (3alpha,5alpha)-3-hydroxypregnan-20-one (3alpha,5alpha-THP, or allopregnanolone) positive cells, but did not alter 3alpha,5alpha-THP immunoreactivity in NAc. These results suggest that P450scc overexpression, and resultant local increase of 3alpha,5alpha-THP within the VTA reduces ethanol reinforcement and consumption. Vector-mediated gene delivery can be used to modulate neuroactive steroid levels and may lead to new therapeutic strategies for alcoholism and other neuropsychiatric disorders. (literal)
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