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Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative behaviors, but not aggression, in MAO A-deficient mice
Bortolato, Marco Godar, Sean C. Tambaro, Simone Li, Felix G. Devoto, Paola Coba, Marcelo P. Chen, Kevin Shih, Jean C.
Bortolato, Marco
Godar, Sean C.
Tambaro, Simone
Li, Felix G.
Devoto, Paola
Coba, Marcelo P.
Chen, Kevin
Shih, Jean C.
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Abstract
Monoamine oxidase (MAO) A, the major enzyme catalyzing the oxidative degradation of serotonin (5-hydroxytryptamine, 5-HT), plays a key role in emotional regulation. In humans and mice, MAO-A deficiency results in high 5-HT levels, antisocial, aggressive, and perseverative behaviors. We previously showed that the elevation in brain 5-HT levels in MAO-A knockout (KO) mice is particularly marked during the first two weeks of postnatal life. Building on this finding, we hypothesized that the reduction of 5-HT levels during these early stages may lead to enduring attenuations of the aggression and other behavioral aberrances observed in MAO-A KO mice. To test this possibility, MAO-A KO mice were treated with daily injections of a 5-HT synthesis blocker, the tryptophan hydroxylase inhibitor p-chloro-phenylalanine (pCPA, 300 mg/kg/day, IP), from postnatal day 1 through 7. As expected, this regimen significantly reduced 5-HT forebrain levels in MAO-A KO pups. These neurochemical changes persisted throughout adulthood, and resulted in significant reductions in marble-burying behavior, as well as increases in spontaneous alternations within a T-maze. Conversely, pCPA-treated MAO-A KO mice did not exhibit significant changes in anxiety-like behaviors in a novel open-field and elevated plus-maze; furthermore, this regimen did not modify their social deficits, aggressive behaviors and impairments in tactile sensitivity. Treatment with pCPA from postnatal day 8 through 14 elicited similar, yet milder, behavioral effects on marble-burying behavior. These results suggest that early developmental enhancements in 5-HT levels have long-term effects on the modulation of behavioral flexibility associated with MAO-A deficiency.
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2013-12
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Elsevier
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Bortolato, M., Godar, S. C., Tambaro, S., Li, F. G., Devoto, P., Coba, M. P., … Shih, J. C. (2013). Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative behaviors, but not aggression, in MAO A-deficient mice. Neuropharmacology, 0, 10.1016/j.neuropharm.2013.07.003. http://doi.org/10.1016/j.neuropharm.2013.07.003