Perinatal MAO Inhibition Produces Long-Lasting Impairment of Serotonin Function in Offspring

Abstract

In addition to transmitter functions, many neuroamines have trophic or ontogenetic regulatory effects important to both normal and disordered brain development. In previous work (Mejia et al., 2002), we showed that pharmacologically inhibiting monoamine oxidase (MAO) activity during murine gestation increases the prevalence of behaviors thought to reflect impulsivity and aggression. The goal of the present study was to determine the extent to which this treatment influences dopamine and serotonin innervation of murine cortical and subcortical areas, as measured by regional density of dopamine (DAT) and serotonin transporters (SERT). We measured DAT and SERT densities at 3 developmental times (PND 14, 35 and 90) following inhibition of MAO A, or MAO B or both throughout murine gestation and early post-natal development. DAT binding was unaltered within the nigrostriatal pathway, but concurrent inhibition of MAO-A and MAO-B significantly and specifically reduced SERT binding by 10–25% in both the frontal cortex and raphe nuclei. Low levels of SERT binding persisted (PND 35, 90) after the termination (PND 21) of exposure to MAO inhibitors and was most marked in brain structures germane to the previously described behavioral changes. The relatively modest level of enzyme inhibition (25–40%) required to produce these effects mandates care in the use of any compound which might inhibit MAO activity during gestation.

The role of monoamine oxidase A in the neurobiology of aggressive, antisocial, and violent behavior: A tale of mice and men

“…This concept highlights the importance of the first week of postnatal life in mice to produce aggressive and antisocial-related behaviors. These data are aligned with previous observations in rodents, which showed that perinatal pharmacological inhibition of MAOA produced impulsive and aggressive responses (Whitaker-Azmitia et al, 1994;Mejia et al, 2002), which are accompanied by long-term perturbations of serotonergic, but not dopaminergic signaling in the cortex and raphe nuclei (Burke et al, 2018). It should be noted that, in mice, the brain expression of the Maoa gene in serotonergic neurons is high during the first four days and progressively declines to reach a minimal level by the third week of postnatal life (Vitalis et al, 2002).…”

The mouse at the popcorn stage of development

“…In the rat striatum, dopamine influenced n‐methyl‐d‐aspartate (NMDA) responses starting only from the third postnatal week (Cepeda & Levine, 1998), implying a role for dopamine‐glutamate interactions during the popcorn stage, and D 1 as well as D 2 receptor density reached a peak on postnatal 40 and then declined to adult levels, a result also found in nucleus accumbens and prefrontal cortex (Andersen et al, 2000), implying a role for dopaminergic receptor supersensitivity underlying neonatal hyperactivity. However, the popcorn stage was unaffected when included in a 14‐part battery of neural function after neonatal monoamine oxidase inhibition in mice (Burke et al, 2018) when one would expect an enhanced response. However, it is possible that the response cannot be enhanced due to a ceiling effect.…”