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Neuropharmacology. 2013 Dec;75:223-32. doi: 10.1016/j.neuropharm.2013.07.003. Epub 2013 Jul 16.

Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative behaviors, but not aggression, in MAO A-deficient mice.

Author information

1
Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, MH 5040, 1251 Wescoe Hall Dr., Lawrence, KS 66045, USA. Electronic address: bortolato@ku.edu.
2
Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
3
"Guy Everett" Laboratory, Dept. of Neuroscience "B.B. Brodie", University of Cagliari, 09124 Monserrato, CA, Italy.
4
Dept. of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
5
Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA; Dept. of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Electronic address: jcshih@usc.edu.

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.

KEYWORDS:

Aggression; Animal models; Early developmental stages; Monoamine oxidase A; Perseverative behaviors; Serotonin

PMID:
23871843
PMCID:
PMC3849223
DOI:
10.1016/j.neuropharm.2013.07.003
[Indexed for MEDLINE]
Free PMC Article

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