Elsevier

Biological Psychiatry

Volume 52, Issue 8, 15 October 2002, Pages 811-822
Biological Psychiatry

Original article
Monoamine oxidase inhibition during brain development induces pathological aggressive behavior in mice

https://doi.org/10.1016/S0006-3223(02)01418-XGet rights and content

Abstract

Background

Monoamine oxidase (MAO) is historically a focus of concern in research on impulsive and aggressive behavior. Recent studies in a single kindred with a point mutation in the MAO-A gene, together with phenotypic evaluations of MAO-A knockout mice, have sharpened this interest. The goal of this study was to investigate the behavioral consequences of MAO inhibition during brain development and to determine the extent to which specific effects could be attributed to MAO- A versus MAO-B.

Methods

MAO-A and B inhibitors were administered, separately or in combination, during gestation and lactation. Behavioral evaluations included neurologic testing, delay of rewarded response, and the resident–intruder aggression paradigm, conducted before and after an acute pharmacologic challenge.

Results

Total prenatal MAO inhibition produced a pervasive increase in aggressive behavior, whereas MAO-B inhibited mice demonstrated a similar pattern of lower intensity. Aggression was elevated in MAO-A inhibited mice only after acute pharmacologic challenge, suggesting prenatal sensitization.

Conclusions

Developmental inhibition of MAO activity engenders behavioral effects that parallel those observed in animals with genetic ablation of MAO function. These data underscore the importance of neurochemical changes during development and provide a possible model for disinhibited aggression, common in clinical populations.

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.

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