Original articleMonoamine oxidase inhibition during brain development induces pathological aggressive behavior in mice
Introduction
In 1993, Brunner et al (1993a) described a kindred in which several male subjects exhibited borderline intelligence and pathologic impulsive aggression. The pattern of inheritance suggested an X-linked disorder. Subsequent analysis revealed a point mutation in exon 8 of the monoamine oxidase A (MAO-A) gene (Brunner et al 1993b), which resulted in complete deficiency of MAO-A activity but normal MAO-B activity (Brunner et al 1993a). The notion that MAO-A deficiency might be related to aggressive behavior was strengthened by studies in experimental animals such as that of Cases et al (1995), in which transgenic MAO-A knockout mice exhibit aggressive behaviors including a shorter latency to attack in a resident–intruder paradigm, compared with wild-type mice, and that by Whitaker-Azmitia et al (1994), in which rat pups were exposed to MAO inhibitors during brain development. The MAO-inhibited rats were impaired in acquiring passive avoidance and spent more time in exposed regions of an open field. This was interpreted as reflecting higher impulsivity, increased sensation-seeking behaviors, and lower anxiety in threatening situations.
Clinically, MAO inhibitors are effective and widely used antidepressants (Kaplan and Sadock 1998), but aggression is not a reported side effect of these drugs. What is the basis for this paradox? Perhaps it is related to the developmental timing of MAO inhibition—pervasive in the Brunner patients, prenatal in the experimental animal studies, and postnatal in patients treated with MAO inhibitors. This conceptualization would be consistent with the developmental expression of MAO activity in which MAO-A appears early, whereas MAO-B is not expressed until after birth and rises sharply during astrocyte proliferation (Weyler et al 1990). In the absence of MAO activity, substrates and alternative metabolites would increase in concentration, and compensatory mechanisms may appear. Our study was designed to investigate the behavioral consequences of inhibition of MAO during embryogeny and early postnatal life and to determine the extent to which specific effects could be attributed to selective or combined inhibition of MAO-A, MAO-B, or both.
Section snippets
Overview
This experiment comprised two phases. In phase one, equal numbers of male and female offspring were studied. In the second phase, a replication using only male offspring confirmed the initial results.
Subjects and drug treatment
Retired CD1 dams were purchased from Charles River Laboratory and received a day after impregnation. After 1 day of adaptation, weight was recorded and continuous administration of medication started. Microsmotic pumps (ALZA 2002; Cupertino, CA) containing one of the following were implanted: 1)
Results
The number of mice born to each dam ranged from 7 to 12. For behavioral testing, each treatment group was culled to comprise 10 male and 5 female subjects. Experimental groups did not differ (p> .05) in body weight (Table 1). There were no morphologic abnormalities in the newborn mice. Neurologic evaluations at 1, 2, and 3 months of age showed the expected developmental changes, which did not differ between groups. No clinically relevant neurologic aberration occurred in any member of the
Discussion
In this study, we have shown that inhibition of MAO during murine development may produce behavioral phenotypes that differ as a function of the quantitative extent of MAO inhibition, and, to a lesser extent, of the specific form of MAO (A vs. B) that has been inhibited. There was no effect of any treatments on either gross morphology or neurologic function, suggesting that these findings are a direct or indirect consequence of inhibiting MAO activity and are not secondary to more general
Acknowledgements
This work was supported through a grant from the Medical Research Council of Canada and a fellowship from the Organization of American States.
References (35)
Modern views on an ancient chemicalSerotonin effects on cell proliferation, migration and apoptosis
Brain Res Bull
(2001)- et al.
The functional role of monoamine oxidases A and B in the mammalian central nervous system
Prog Neurol
(1994) - et al.
Lack of barrels in the somatosensory cortex of monoamine oxidase A deficient miceRole of a serotonin excess during the critical period
Neuron
(1996) - et al.
Subchronic treatment of rats with nicotineeffects on tolerance and on [3H]acetylcholine and [3H]nicotine binding in the brain
Drug Alcohol Depend
(1986) - et al.
In vitro and in vivo inhibition by benserazide of clogyline-resistant amine oxidase in rat cardiovascular tissues
Biochem Pharmacol
(1982) - et al.
Different test situations for measuring offensive aggression in male rats do not result in the same wound patterns
Physiol Behav
(1984) - et al.
Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus
Neuroscience
(2000) - et al.
Cerebral cortical blood flow maps are reorganized in MAO-B deficient mice
Brain Res
(1999) - et al.
Selegiline enhances NGF synthesis and protects the central nervous system from excitotoxic and ischemic damage
Eur J Pharmacol
(1996) - et al.
Biochemistry and genetics of monoamine oxidase
Pharmacol Ther
(1990)