It is now clearly established that the neurotransmitter serotonin acts as a developmental signal in the maturing brain prior to assuming its role in neurotransmission. Our work suggests that this action is mediated through the presence of two high affinity serotonin receptors in the fetal brain. We have hypothesized that these receptors are the 5-HT1a and 5-HT1b receptors which have been characterized in the adult brain. Our work in now concerned with more clearly determining the role each receptor plays and the biochemical, morphological and behavioral consequences of that role. Our study will begin by using radioligand binding assays to characterize the receptors which occur in various regions of the developing rat brain. We will use the radioligands 3H-PAT (for 5- HT1a) and 125I-CYP (for 5-HT1b) in saturation analysis studies in tissues taken from 14 day embryos up to 30 days post-natal. On the basis of these studies, we will test the abilities of selective agonists (PAT for 5-HT1a and TFMPP for 5-HT1b) to alter neuronal development in a tissue culture model of serotenergic neurons. This model will be assessed biochemically (by specific high affinity uptake of 3H-serotonin) and morphologically (by immunocytochemistry, using an antibody raised against serotonin, and morphometric analysis). Our work will then return to the whole animal, where we will study the distribution and pharmacokinetics of the selective agonists in rat fetuses, after maternal administration. This information will enable us to accurately deliver to the fetus the concentrations of agonist which have been shown in tissue culture to alter neuronal development. The offspring will be assessed biochemically, morphologically and behaviorally for developmental abnormalities. As a result of our work, we will gain insights into human developmental disorders such as Down's syndromes and autism, where serotonergic abnormalities are known to occur.
| Whitaker-Azmitia, P M; Molino, L J; Caruso, J et al. (1990) Serotonergic agents restore appropriate decision-making in neonatal rats displaying dopamine D1 receptor-mediated vacillatory behavior. Eur J Pharmacol 180:305-9 |
