UNILATERAL DESTRUCTION OF DOPAMINE PATHWAYS INCREASES IPSILATERAL STRIATAL SEROTONIN TURNOVER IN RATS

In order to evaluate the influence of dopaminergic transmission on regional brain utilization of serotonin (5HT), the effects of the destruction of the ascending dopamine (DA) pathways on regional brain 5HT metabolism in the rat were examined. Complete unilateral lesions of the nigrostriatal DA pathways (>90% DA loss) were made by infusing the neurotoxin 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 index of 5HT turnover) increased by more than 90%. In the same rats, cortical and hypothalamic 5HT, 5HIAA, and 5HT turnover were not changed as a result of the MFB or SN lesions. These results suggest that the loss of DA innervation in the striatum triggers an increase in 5HT turnover 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 examined the effect of intracerebral implantation of DA-containing pellets into one group of MFB-lesioned rats. The lesioned rats with placebo pellets did not differ from lesioned rats without pellets, whereas the implantation of DA pellets reversed the lesion-induced changes in the 5HT levels and 5HIAA:5HT ratios. It appears that DA normally acts to inhibit 5HT release in the striatum. Accordingly, the loss of DA innervation results in overactive 5HT transmission, which leads to a net depletion of 5HT stores. As striatal 5HT levels and turnover can be restored to normal by sustained infusion of DA in the lesioned rats, the presence of DA in the striatum appears crucial for the maintenance of normal 5HT function. (C) 1994 Academic Press, Inc.