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Neuropharmacology. 2014 Feb;77:177-84. doi: 10.1016/j.neuropharm.2013.09.010. Epub 2013 Sep 22.

Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice.

Author information

  • 1Department of Cell Biology, Duke University, Durham, NC 27710, USA. Electronic address: Benjamin.sachs@dm.duke.edu.
  • 2Department of Cell Biology, Duke University, Durham, NC 27710, USA; Research Scholars Program, Duke University, Durham, NC 27710, USA. Electronic address: Aylin.salahi@duke.edu.
  • 3Department of Cell Biology, Duke University, Durham, NC 27710, USA; Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: m.caron@cellbio.duke.edu.

Abstract

Serotonergic dysfunction has been hypothesized to play an important role in the pathophysiology of alcoholism. However, whether congenital serotonin (5-HT) deficiency leads to increased alcohol consumption or affects ethanol-related behaviors has not been established. Here, we use a transgenic mouse line that expresses a hypofunctional variant of the 5-HT synthesis enzyme, tryptophan hydroxylase 2, to examine the impact of 5-HT deficiency on responses to alcohol. We demonstrate that these 5-HT-deficient transgenic animals (Tph2KI mice) recover their righting reflex more rapidly than wild-type controls following a high dose of ethanol and exhibit blunted locomotor retardation in response to repeated ethanol administration. In addition, compared to WT controls, 5-HT-deficient animals consume significantly more ethanol and exhibit increased preference for ethanol in two-bottle choice tests. Our data also suggest that 5-HT plays a critical role in mediating the effects of ethanol on Akt/GSK3β signaling in the nucleus accumbens. Overall, our results corroborate previous theories regarding the importance of brain 5-HT levels in mediating responsiveness to alcohol and demonstrate, for the first time, that congenital 5-HT deficiency leads to increased ethanol consumption and decreased sensitivity to the sedative-like effects of ethanol, perhaps in part through modulating Akt/GSK3β signaling.

Copyright © 2013 Elsevier Ltd. All rights reserved.

KEYWORDS:

Alcohol; Behavior; ETOH; IP; NAc; Serotonin; Tph2; Tph2KI; Tryptophan hydroxylase 2; WT; ethanol; intra-peritoneal; nucleus accumbens; tryptophan hydroxylase 2; tryptophan hydroxylase 2 R439H knock-in; wild-type

PMID:
24067926
[PubMed - in process]
PMCID:
PMC3874885
[Available on 2015/2/1]
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