Effects of Gestational Exposure to Monoamine Oxidase Inhibitors in Rats: Preliminary Behavioral and Neurochemical Studies

Abstract

Monoamine neurotransmitters are important in the development of the immature mammalian brain, prior to assuming their role as neurotransmitters. The endogenous levels of these transmitters are highly regulated by the enzyme monoamine oxidase (MAO). Thus, any change in this enzyme should have a profound effect on brain development. In order to test this hypothesis, we treated developing rat pups with the monoamine oxidase inhibitors (MAO-Is), dorgyline (MAO-A, 3 mg/kg), and deprenyl (MAO-B, 3 mg/kg) throughout gestation (MAO-I-birth), or throughout gestation and to sacrifice (MAO-I-sac). The animals were analyzed for serotonin and dopamine terminal density, using 3H-paroxetine and 3H-GBR 12935, respectively. Whereas there were no changes in the development of the dopamine system, the serotonin system was severely KEYWORDS: Serotonin; Monoamine oxidase; Monoamine oxidase inhibitors; Deprenyl; Clorgyline; Neurodevelopment; Impulsivity; Hyperactivity; Norrie's disease. affected, particularly in the cortex that showed a significant reduction of innervation at 30 days postnatal. The animals reached all normal development milestones on schedule, and had no changes in measures of anxiety (% light/dark); however, the animals showed increased open field activity and deficits in a passive avoidance paradigm, which may be a measure of impulsivity. The MAO-I-sac animals were severely impaired, showing stereotypic behavior, seizures, and eventually visual impairments. Our results are discussed in terms of relevance to human disease states, such as atypical Norrie's disease, impulsivity, and hyperactivity. As well, our results should be used to caution against the use of MAO-Is in women of child-bearing age.

Specific genetic deficiencies of the A and B isoenzymes of monoamine oxidase are characterized by distinct neurochemical and clinical phenotypes.

“…Further support for involvement of altered 5-HT metabolism is provided by another recent study, in which behavioral disturbances in rats administered MAO inhibitors, before and after birth, were also associated with structural changes in brain serotoninergic systems (48). We have previously argued that the possible disruptive effect of raised 5-HT levels on the developing brain may help explain why impulsive aggressive behavior has been consistently associated with low levels of 5-HT or its primary metabolite, 5-hydroxyindolacetic acid, whereas 5-HT levels are elevated in subjects with selective MAO-A deficiency who show similar behavior (49).…”

Evidence That Brain MAO A Activity Does Not Correspond to MAO A Genotype in Healthy Male Subjects

“…The MAO A genotype may be the main variable regulating developmental catecholamine levels including those of serotonin, known to be crucial for brain development particularly because MAO B develops later than MAO A and would not be present to compensate for deficient MAO A (Shih et al 1999). Compelling evidence suggests that the absence of MAO A during development results in an aggressive phenotype in both animals (Cases et al 1995;Mejia et al 2002;Whitaker-Azmitia et al 1994) and humans (Brunner et al 1993). In contrast there is evidence of aggression as a side effect in adults treated with MAO A-inhibiting drugs, and in rodents MAO A inhibition in adulthood reduces stress-induced aggression (Ossowska et al 1999).…”

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

“…169 Several drug treatment studies have shown this negative feedback of 5-HT on development of 5-HTergic neurons. [170][171][172][173][174][175][176][177][178][179][180] Alterations in 5-HTT function 181 and hypothalamic 5-HT levels 182 may be in part responsible for altered HPA axis activity in adult PS offspring. 183 PS may lead to an altered set-point of the HPA axis and 5-HT system, increasing susceptibility to later (depressive) disorders.…”