Developmental Brain Research, 59 (1991) 59-63 © 1991 Elsevier Science Pubhshers B V (Biomedical Dlwslon) 0165-3806/91/$03 50 ADONIS 016538069151234B BRESD 51234 59 Dose-related effects of prenatal 5-methoxytryptamine (5-MT) on development of serotonin terminal density and behavior A.V. Shemer 1, E.C. Azmitia 2 and P.M. Whitaker-Azmitia 1. 1Department of Psychtatry and Behavioral Sctence, State Untverstty of New York, Stony Brook, NY 11794 (U S A ) and 2Department of Btology, New York Umverstty, New York, N Y 10003 (U S A ) (Accepted 4 December 1990) Key words Serotonm; Neuronal development, Behavioral development, Serotonm receptor Our prewous studies with a t~ssue culture model of neuronal development have shown that the development of serotomn neurons IS dependent, at least m part, on the stimulation of high affinity serotonln receptors One receptor inhibits the outgrowth of neurons, while the other promotes it The present study was therefore undertaken to rephcate these hndmgs in a whole animal model system Pregnant Sprague-Dawley rats were treated from gestatlonal day 12 untd birth with 0 1, 1 0 or 3 0 mg/kg 5-methoxytryptamme (5-MT) The pups were assessed for serotonin outgrowth by the selectwe synaptosomal uptake of [3H]serotonm at postnatal days 1, 15 and 30 (D1, D15, D30) In addmon, the pups were tested behaviorally for the neonatal serotonm syndrome at D5 (induced by qmpazme), spontaneous alternaUon and open held actlwty at day 15 and hck suppressmn at day 30 At 1 0 mg/kg, the terminal outgrowth of serotonln neurons was inhibited, whde the highest dose, 3 0 mg/kg, showed stimulation of outgrowth The highest dose caused behavioral alterations which had abated by 30 days, while the mtermedlate dose (1 0 mg/kg) showed behaworal changes throughout Interestingly, the lowest dose, 0 1 mg/kg, showed changes In uptake only at D1 and behavioral changes only at later timepolnts, principally at D30 This suggests that serotonm not only plays a role in regulating the development of the neurons which produce it, but that it may also play a role in neurochemlcal imprinting-that is, changes m behavior in the adult may be due to changes m neurochemlstry dunng development, even though that neurochemlstry may have been corrected by the t~me the ammal becomes an adult INTRODUCTION Serotonm (5-hydroxytryptamlne; 5-HT) has been pro- posed as a regulator of neuronal development 5 In a tissue culture model of developing serotonln neurons, utlhzing 14-day embryonic fetal rat raphe cells, we have previously shown that the serotonln agonist 5-me- thoxytryptamine (5-MT) can cause stunting of neuronal processes or enhancement of outgrowth in a dose- dependent manner 13 On the basts of this, we have proposed that two receptors are revolved in regulating the development of serotonm neurons, and that these receptors are tn fact 'antagonistic' to each other. We, and others, have shown that such fetal receptors do occur, and that they are capable of respondmg to stimulatton by 5_MT12.14. In whole animal studies we have shown that prenatal administration of 5-MT (1 mg/kg dally) inhibits the development of serotonln terminals and has consequent effects on behaviors 11 The present experiments were carried out in order to determine a dose-response to 5-MT, in an attempt to replicate, in whole animal studies, the dual effects of this drug described m tissue culture ~3 As well, we have examined more behaviors, In order to further delineate the functional consequences of changes in serotonerglc growth We now report that varying doses of a serotonin agonist administered prenatally can indeed have opposite effects on development of serotonin nerve terminals m the offspring, as measured by the specific synaptosomal uptake of [3H]serotonln. However, the subsequent ef- fects on behavior are complex, depending not only on prenatal dose but also on day of testing Moreover, behavioral changes are evident in animals for which no changes in uptake measures were found MATERIALS AND METHODS Ammal preparatton Pregnant Sprague-Dawley rats on their s~xth day of gestation were obtained from Tacomc Farms and maintained on a 12-h hght/dark cycle at a temperature of 22 °C Each rat was housed individually, with rat chow and water avadable ad llb~tum All administration of drugs to the dams began on the twelfth day of gestation and terminated at partuntLon L~tters were culled to 10 Correspondence P M Whltaker-Azmltla, Department of Psychiatry and Behavioral Science, State Umverslty of New York, Stony Brook, New York, 11794, U S A