Congenital brain serotonin deficiency leads to reduced ethanol sensitivity and increased ethanol consumption in mice.
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.
Department of Cell Biology, Duke University, Durham, NC 27710, USA. Electronic address: Benjamin.sachs@dm.duke.edu.
Benjamin D
BD
Sachs
Department of Cell Biology, Duke University, Durham, NC 27710, USA; Research Scholars Program, Duke University, Durham, NC 27710, USA. Electronic address: Aylin.salahi@duke.edu.
A Ayten
AA
Salahi
Department 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.
Marc G
MG
Caron
D000428:Alcohol Drinking / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D057897:Reflex, Righting / Q000187:drug effects / Q000235:genetics; D012701:Serotonin / Q000172:deficiency*; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000378:metabolism
D012701:Serotonin; D000431:Ethanol; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
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