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The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake
Godar, Sean C. ; Bortolato, Marco ; Castelli, M. Paola ; Casti, Alberto ; Casu, Angelo ; Chen, Kevin ; Ennas, M. Grazia ; Tambaro, Simone ; Shih, Jean C.
Godar, Sean C.
Bortolato, Marco
Castelli, M. Paola
Casti, Alberto
Casu, Angelo
Chen, Kevin
Ennas, M. Grazia
Tambaro, Simone
Shih, Jean C.
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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 5-HTT blocker fluoxetine (10 mg/kg, i.p.) reduced aggressive behavior in MAO-A knockout (KO) mice and social deficits in hypomorphic MAO-ANeo 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-ANeo 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.
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Date
2014-09
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Elsevier
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Keywords
Serotonin, Monoamine oxidase, Serotonin transporter, Animal models
Citation
Godar, S. C., Bortolato, M., Castelli, M. P., Casti, A., Casu, A., Chen, K., … Shih, J. C. (2014). The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake. Journal of Psychiatric Research, 56, 1–9. http://doi.org/10.1016/j.jpsychires.2014.04.014