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.

Keywords: MAO inhibition; aggression; anxiety; dopamine transporter; neurodevelopment; serotonin transporter.

Figure 1

SERT Binding Densities. MAO inhibition with combined clorgyline and deprenyl (AB), as described in detail in the text, reduced SERT binding in the cortex (F_3,52 = 3.59, p = 0.02) and the raphe nuclei (F_3,51 = 6.07, p = 0.0015) in both a time- and treatment-dependent fashion. Significant pairwise time x treatment effects (p < 0.05) are indicated by *. In the cortex, AB was significantly different from all other groups (post-hoc p < 0.05); in raphe, AB was significantly different from C and A, and B was also significantly different from C (post-hoc p < 0.05). Six animals were examined for each treatment and each time point; error bars S.E.M.