Prenatal treatment with a selective D 1 receptor agonist (SKF 38393) alters adult [ 3H]paroxetine binding and dopamine and serotonin behavioral sensitivity

Abstract

We have previously shown that the development of serotonin neurons can be affected by various pharmacological agents acting on the serotonin system. Receptor stimulation by high doses of 5-methoxytryptamine (5-MT) causes increased outgrowth, through release of an astroglial growth factor, while a low concentration of 5-MT has a direct inhibitory effect on neuronal outgrowth. Since 5-MT is known to be a release-regulating autoreceptor agonist, the present study was aimed at testing the hypothesis that inhibition of serotonin release causes the inhibition of outgrowth. We used the D 1 receptor agonist SKF 38393 as an inhibitor of serotonin release. Pregnant Sprague-Dawley rats were treated with SKF 38393 (1 mg/kg; subcutaneously) from gestational day 12 until parturition. Development of serotonin terminal outgrowth was evaluated in the offspring using the selective uptake marker [ 3H]paroxetine in brainstem and frontal cortex. In saline and SKF 38393 treated animals, the developmental pattern in the frontal cortex showed the highest terminal density at day 60 and a return to normal by day 90, with no statistically significant differences between the groups. Conversely, in the brainstem, [ 3H]paroxetine binding developed normally until postnatal day 90, when the SKF 38393 pretreated animals showed only 58% of the binding observed in saline animals. In a fixed interval responding task, given at day 90, both dopamine and serotonin receptor systems have significantly decreased sensitively after the SKF 38393 pretreatment. In conclusion, our results show that the inhibitory effects of serotonin on the growth of serotonin neurons, may be through inhibition of neurotransmitter release. Moreover, we propose a means by which serotonin and dopamine systems could be interdependent during development.