ALTERED DOPAMINE AND SEROTONIN METABOLISM IN THE DOPAMINE-DENERVATED AND SEROTONIN-HYPERINNERVATED NEOSTRIATUM OF ADULT-RAT AFTER NEONATAL 6-HYDROXYDOPAMINE

3,4-Dihydroxyphenylalanine (L-DOPA), 5-hydroxy-1-tryptophan (5-HTP), dopamine (DA), 5-hydroxytryptamine (5-HT) and their metabolites were measured in the rostral neostriatum of adult rats neonatally lesioned with 6-hydroxydopamine (6-OHDA) after treatment with NSD-1015 (aromatic L-amino acid decarboxylase inhibitor), pargyline (monoamine oxidase inhibitor) or probenecid (blocker of acidic metabolite efflux). Binding experiments with DA and 5-HT transporter ligands allowed us to relate observed changes to the number of DA and 5-HT terminals. One and 3 months after the lesions were made, DA, 3,4-dihydroxyphenyl-acetic acid (DOPAC)- and homovanillic acid (HVA)-content as well as [H-3]N-[1-(2-benzo(b)-thiophenyl)cyclohexyl]piper ([H-3]BTCP) binding were lowered to 1% to 2% of control values, reflecting a permanent DA denervation. After 1 month, 5-HT content was increased by 96% and 5-hydroxyindole-3-acetic acid (5-HIAA) was increased by 50% in the presence of control levels of [H-3]citalopram binding, suggesting that there was an increased amount of 5-HT per neostriatal 5-HT terminal. At 3 months, 5-HT content had increased by 205%, 5-HIAA remained increased by 50% and [H-3]citalopram binding had reached 170% of control values, indicating a persistent increase in 5-HT content within an excessive number of 5-HT terminals (hyperinnervation). At both survival times, neostriatal L-DOPA accumulation after NSD-1015 was low, but ratios of L-DOPA to DA and of L-DOPA to [H-3]BTCP were greatly elevated. 5-HTP accumulation was increased, but ratios of 5-HTP to 5-HT were lower than control, despite unchanged ratios of 5-HTP to [H-3]citalopram. At 3 months, neostriatal DA accumulation after pargyline was also low but considerably increased over control when expressed as percentage of the initial value. In contrast, 5-HT accumulation was not different from control and actually decreased when expressed as percentage of the initial value. After pargyline or probenecid, HVA and DOPAC levels suggested a shift of DA catabolism from intracellular to extracellular, presumably due to a greater DA release per terminal. Thus, DA turnover was significantly increased within residual DA terminals. 5-HT synthesis and catabolism were unaffected, but a significant increase in the amount of 5-HT per terminal had occurred before the 5-HT hyperinnervation, perhaps imputable to an up-regulation of 5-HT1B release-modulating autoreceptors.