Age-related changes in the monoaminergic neuron systems in the brains of methylazoxymethanol acetate (MAM)-induced micrencephalic rats were studied. Neurochemical analysis revealed high levels of serotonin, norepinephrine and associated metabolites in several brain areas of MAM-treated rats. In particular, serotonin levels in the frontal cortex, cingulate cortex and hippocampus of 12-month-old (12 M) MAM-treated rats were significantly higher than in corresponding age-matched controls. Immunohistochemical analysis demonstrated numerous aberrant serotonin-immunoreactive fibers and small numbers of aberrant tyrosine hydroxylase-immunoreactive fibers in the septum, caudate putamen, thalamus, cerebral cortex, hippocampus and midbrain tegmentum of 12 M MAM-treated rats. Aberrant monoaminergic fibers characterized by swollen varicosities and thickening of intervaricose segments were common compared to 12 M control rats. In the cortex and hippocampus of 12 M MAM-treated rats, aberrant fibers were observed near cortical heterotopic tissue. These results indicate early onset of age-related degeneration of monoaminergic fibers in micrencephalic rats. Aged MAM-treated rats may thus offer a good model for studying age-related monoaminergic changes in the cortical heterotopic tissue of human cortical malformations.