In order to evaluate the influence of dopaminergic transmission on reg
ional brain utilization of serotonin (5HT), the effects of the destruc
tion of the ascending dopamine (DA) pathways on regional brain 5HT met
abolism in the rat were examined. Complete unilateral lesions of the n
igrostriatal DA pathways (>90% DA loss) were made by infusing the neur
otoxin 6-hydroxydopamine into either the left medial forebrain bundle
(MFB) or the left substantia nigra (SN). At 6 weeks: after the lesions
, levels of 5HT and its major metabolite, 5-hydrorryindoleacetic acid
(5HIAA), were determined bilaterally in the striatum, frontal cortex,
and hypothalamus. In the striatum of the lesioned hemisphere, the 5HT
level decreased by more than 50%, while the ratio of 5HIAA:5HT (an ind
ex of 5HT turnover) increased by more than 90%. In the same rats, cort
ical and hypothalamic 5HT, 5HIAA, and 5HT turnover were not changed as
a result of the MFB or SN lesions. These results suggest that the los
s of DA innervation in the striatum triggers an increase in 5HT turnov
er and a net depletion of 5HT in the striatum. To verify that the loss
of DA was responsible for the observed striatal 5HT changes, we exami
ned the effect of intracerebral implantation of DA-containing pellets
into one group of MFB-lesioned rats. The lesioned rats with placebo pe
llets did not differ from lesioned rats without pellets, whereas the i
mplantation of DA pellets reversed the lesion-induced changes in the 5
HT levels and 5HIAA:5HT ratios. It appears that DA normally acts to in
hibit 5HT release in the striatum. Accordingly, the loss of DA innerva
tion results in overactive 5HT transmission, which leads to a net depl
etion of 5HT stores. As striatal 5HT levels and turnover can be restor
ed to normal by sustained infusion of DA in the lesioned rats, the pre
sence of DA in the striatum appears crucial for the maintenance of nor
mal 5HT function. (C) 1994 Academic Press, Inc.