Regional distribution of the 5-HT innervation in the brain of normal and lurcher mice as revealed by [3H]citalopram quantitative autoradiography.

The neurological cerebellar mutant lurcher is characterized by a primary degeneration of Purkinje cells as well as retrograde secondary partial degeneration of cerebellar granule cells and inferior olivary neurons. Since serotonin (5-HT) has been implicated in the modulation of excitatory amino acid systems of the cerebellum, the 5-HT innervation of the normal and lurcher mice was examined by quantifying uptake sites using [3H]citalopram autoradiography, and by biochemical assays of the indoles 5-HT, 5-hydroxy-L-tryptophan and 5-hydroxyindole-3-acetic acid using high-performance liquid chromatography. Comparable results were found between [3H]citalopram binding and 5-HT tissue concentrations in different brain regions. The highest [3H]citaslopram labelling was observed in defined structures of the mesencephalic and upper pontine regions, in limbic strutures, in hypothalamus and in discrete thalamic divisions, while the lowest labelling of uptake sites was documented in cerebellum and brainstem reticular formation. In lurcher mutants, the histology confirmed cell degeneration and the reduction in width, leading to 65%, 45% and 25% atrophies of total cerebellum, deep nuclei and inferior olivary nucleus, respectively. The [3H]citalopram labelling corrected for surface loss was 45% and 20% higher to cerebellar deep nuclei and red nucleus, respectively, but remained unchanged in the cerebellar cortex and inferior olivary nucleus. Moreover, higher labelling was found in nucleus raphe dorsalis, ventral tegmental area, inferior colliculus, locus coeruleus, pontine central grey and anterior thalamic nuclei, areas known to be part of cerebellar afferent and efferent systems. The present results indicate that in such pathological conditions as described for the lurcher mutant, the 5-HT system may modulate motor function not only at the level of the cerebellum, but also in other forebrain structures functionally related to the motor system.