PLASTICITY AND ONTOGENY OF THE CENTRAL 5-HT TRANSPORTER - EFFECT OF NEONATAL 5,7-DIHYDROXYTRYPTAMINE LESIONS IN THE RAT

5,7-Dihydroxytryptamine (5,7-DHT) is unique as a serotonin (5-HT) neurotoxin in that i.p. injection of neonatal rats increases concentrations of 5-HT in brainstem while depleting 5-HT in cortex, hippocampus and spinal cord. To study the mechanism of this effect we measured the 5-HT transporter or uptake site, a presynaptic marker, using [H-3]paroxetine binding. There were significant regional differences in B(max) of vehicle-injected rats: brainstem, diencephalon > striatum, cortex, spinal cord > hippocampus, cerebellum. There were also regional differences in the ontogeny of bindings sites: at postnatal day 7, [H-3]paroxetine sites were 39% of adult levels in cortex compared to 63% in brainstem. Thirty days after 100 mg/kg 5,7-DHT i.p., B(max) of [H-3]paroxetine binding was significantly increased in brainstem (+67%) and diencephalon (+136%), whereas it decreased in cortex (-59%), hippocampus (-94%) and spinal cord (-99%), striatum (-41%) and cerebellum (-37%). K(D) remained unaltered. In dose-response studies (0-200 mg/kg), 50 mg/kg was the threshold dose for B(max) effects and 200 mg/kg was lethal. In weekly time-course studies, changes were apparent 1 week after 5,7-DHT lesions. Binding site increases in diencephalon and brainstem were not maximal until 3 weeks after injection, whereas percent decreases in cortical sites remained unchanged at each week studied. Lesion effects on the ontogeny of [H-3]paroxetine binding sites were region-dependent: cortical sites continued to increase with age but spinal sites did not. There was no significant recovery in spinal cord. These data show significant regional, dose- and time-dependent effects of neonatal 5,7-DHT lesions made by i.p. injection on [H-3]paroxetine binding sites. They are evidence for brainstem 5-HT hyperinnervation (sprouting) as a cause of increased 5-HT concentrations rather than other mechanisms following neonatal i.p. 5,7-DHT injections.