title: Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative behaviors, but not aggression, in MAO A-deficient mice.
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.
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
authors.affiliation: Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Godar
authors.affiliation: Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Tambaro
authors.affiliation: Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Felix G
authors.initials: FG
authors.lastname: Li
authors.affiliation: "Guy Everett" Laboratory, Dept. of Neuroscience "B.B. Brodie", University of Cagliari, 09124 Monserrato, CA, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Dept. of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Marcelo P
authors.initials: MP
authors.lastname: Coba
authors.affiliation: Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
mesh_terms: D000161:Acoustic Stimulation; D000367:Age Factors; D000374:Aggression / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001008:Anxiety Disorders / Q000139:chemically induced; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D010134:Fenclonine / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011597:Psychomotor Performance / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D012701:Serotonin; D008995:Monoamine Oxidase; D010134:Fenclonine
keywords: Aggression; Animal models; Early developmental stages; Monoamine oxidase A; Perseverative behaviors; Serotonin