Developmental psychopharmacology in child and adolescent psychiatry: results of experimental animal studies with fluoxetine and methylphenidate in rats

Abstract

Despite an increasing use of clinically effective psychoactive medications in child and adolescent psychiatry, possible effects of such treatments on brain development and the maturation of monoaminergic systems have not been investigated systematically, In a series of experimental animal studies we studied the possible long-term effects of subchronic administration of two widely and successfully used drugs for the treatment of child psychiatric disorders on the maturation of the monoaminergic systems in the developing rat brain. The drugs (either fluoxetine or methylphenidate) were administered via the drinking water for a period of two weeks to very young and somewhat older rats and the effect of these treatments on the density of monoaminergic transporters as a measure of innervation density was measured by ligand-binding assays. A significant increase (by 20%) in the density of serotonin-transporters was found in the frontal cortex (but not in other brain regions) of early fluoxetine-treated rats. This increase persisted into adulthood, without any further treatment. Administration of the psychostimulant methylphenidate for two weeks to very young rats decreased the density of dopamine-transporters in the striatum (but not in the midbrain). This decline reached almost 50% at adulthood, i.e. long after termination of the treatment. No such effect was observed upon the same treatment in older (pubertal) rats. Even though the degree of maturity of the rat brain during the first few weeks after weaning can hardly be related to the normal maturation of the human brain during childhood and adolescence, two cautious conclusions can be drawn from our observations: First, the administration of fluoxetine and methylphenidate during periods when the central serotonergic and dopaminergic systems are still rather plastic and not yet fully elaborated may trigger adaptive responses which are different from those caused by the same treatment at later, more mature developmental stages. And, second, these early drug-induced changes may persist until adulthood.