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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acoustic Stimulation
  • Age Factors
  • Aggression / physiology*
  • Animals
  • Animals, Newborn
  • Anxiety Disorders / chemically induced
  • Behavior, Animal / physiology*
  • Brain / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Exploratory Behavior / drug effects
  • Female
  • Fenclonine / pharmacology
  • Maze Learning / drug effects
  • Mice
  • Mice, Knockout
  • Monoamine Oxidase / deficiency*
  • Monoamine Oxidase / genetics
  • Mutation / genetics
  • Psychomotor Performance / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Serotonin / metabolism*

Substances

  • Enzyme Inhibitors
  • Receptors, N-Methyl-D-Aspartate
  • Serotonin
  • Monoamine Oxidase
  • Fenclonine