Autoregulation of fetal serotonergic neuronal development: Role of high affinity serotonin receptors

A microculture technique was used to study the factors regulating the development of fetal rat serotonergic neurons. Mesencephalic raphe cells from E14 rats co-cultured with hippocampal cells from E18 were grown for up to 4 days in the presence of various agents known to alter serotonergic function in the mature brain. Pargyline (a non-specific monoamine oxidase inhibitor) alone and with serotonin (10^-8 to 10^-6 M) both inhibited growth of serotonergic neurons as assessed by uptake of [³H]serotonin. 5-methoxytryptamine (5-MT), a serotonin agonist with selectivity for serotonin autoreceptors, inhibited growth at low concentrations, but this inhibition was overcome at higher concentrations. Using immunocytochemistry with a primary anti-serotonin antibody, 5-MT was observed to produce stunted processes, increase autoinnervation and lead to neuronal death. A model is proposed whereby high affinity serotonin receptors in fetal brainstem tissue and in fetal forebrain tissue regulate direction and extent of growth. We have confirmed the presence of these receptors using a direct binding assay.