Pharmacological and ultrastructural maturation of serotonergic synapses during ontogeny.

Studies were made on the course of maturation of serotonergic synapses during ontogeny in rat brain. Mature synaptosomes containing the same five types of synatic vesicles as in the adult, including small dense core vesicles, could be isolated in low proportion from the brain of 1-day-old rats. Although the buoyant density of these synaptosomes varied more than in the adult, the 5-hydroxytryptamine (5-HT) synaptosomes at the two age groups had similar sedimentation characteristics. Ouabain and imipramine, which block active transport of 5-HT, and reserpine, which blocks its granular storage, resulted respectively in a similar slight inhibition of uptake and accumulation of (-14C)5-HT in synaptosomes of 19-day foetuses. Transport and storage of (-14C)5-HT in the brain stem matured simultaneously with endogenous 5-HT content. In subcellular fractionation of the brain 5-HT content, the percentage of 5-HT in the supernatant was significantly lower in neonatal than in adult rats. After treatments with monoamine oxidase inhibitors (MAOIs) and reserpine plus MAOI, respectively, the maximum brain content and subcellular distribution of 5-HT were similar in 1-day-old and adult rats; the result suggests the existence of some other binding mechanism besides the Mg++-ATP-dependent granular storage. Imipramine and N,N-dimethyltryptamine, which cause stimulation of 5-HT receptors, decreased the turnover of brain 5-HT by 40% in adults but had no effect in neonatal rats. Immobilization increased the turnover of brain 5-HT by 35% in adults but had no effect in neonatal rats, whereas fasting increased it by 20% in adults and by 150% in neonatal rats. At 3 weeks of age the responses to imipramine, immobilization and fasting resembled those seen in adults. These responses occurred later than the appearance of the endogenous content, transport and storage of 5-HT and may require maturation of synaptic junctions, the latest neuronal structures to develop.