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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