title: The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake.
abstract: The termination of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is regulated by its uptake by the 5-HT transporter (5-HTT), as well as its degradation by monoamine oxidase (MAO)-A. MAO-A deficiency results in a wide set of behavioral alterations, including perseverative behaviors and social deficits. These anomalies are likely related to 5-HTergic homeostatic imbalances; however, the role of 5-HTT in these abnormalities remains unclear. To ascertain the role of 5-HTT in the behavioral anomalies associated to MAO-A deficiency, we tested the behavioral effects of its blocker fluoxetine on perseverative, social and aggressive behaviors in transgenic animals with hypomorphic or null-allele MAO-A mutations. Acute treatment with the 5-HTT blocker fluoxetine (10 mg/kg, i.p.) reduced aggressive behavior in MAO-A knockout (KO) mice and social deficits in hypomorphic MAO-A(Neo) mice. Furthermore, this treatment also reduced perseverative responses (including marble burying and water mist-induced grooming) in both MAO-A mutant genotypes. Both MAO-A mutant lines displayed significant reductions in 5-HTT expression across the prefrontal cortex, amygdala and striatum, as quantified by immunohistochemical detection; however, the down-regulation of 5-HTT in MAO-A(Neo) mice was more pervasive and widespread than in their KO counterparts, possibly indicating a greater ability of the hypomorphic line to enact compensatory mechanisms with respect to 5-HT homeostasis. Collectively, these findings suggest that the behavioral deficits associated with low MAO-A activity may reflect developmental alterations of 5-HTT within 5-HTergic neurons. Furthermore, the translational implications of our results highlight 5-HT reuptake inhibition as an interesting approach for the control of aggressive outbursts in MAO-A deficient individuals.
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA; Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Godar
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA. Electronic address: bortolato@ku.edu.
authors.forename: Marco
authors.initials: M
authors.lastname: Bortolato
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, CA, Italy.
authors.forename: M Paola
authors.initials: MP
authors.lastname: Castelli
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, CA, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Casti
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, CA, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Casu
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, CA, Italy.
authors.forename: M Grazia
authors.initials: MG
authors.lastname: Ennas
authors.affiliation: Dept. of Cell and Neurobiology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Tambaro
authors.affiliation: Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA; Dept. of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA. Electronic address: jcshih@usc.edu.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Shih
mesh_terms: D000374:Aggression / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D005473:Fluoxetine / Q000494:pharmacology*; D006120:Grooming / Q000187:drug effects / Q000502:physiology; D008297:Male; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008995:Monoamine Oxidase / Q000172:deficiency* / Q000235:genetics; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D005473:Fluoxetine; D008995:Monoamine Oxidase; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Animal models; Monoamine oxidase; Serotonin; Serotonin transporter