Up-regulation of 5-hydroxytryptamine 2 and neurokinin-1 receptors associated with serotonin/substance P hyperinnervation in the rat inferior olive

Abstract

The fate of serotonin and substance P receptors following serotonin/substance P hyperinnervation of CNS tissue was investigated in the inferior olivary complex of adult rats subjected to earlier intraventricular administration of 5,6-dihydroxytryptamine. [ 3H]8- hydroxy-2-(Dl-n- propylamino)tetralin , [ 3H]5-hydroxytryptamine, [ 3H]ketanserin and [ 125I]Bolton-Hunter-substance P were respectively used to label 5-hydroxytryptamine 1A, 5-hydroxytryptamine 1B, 5-hydroxytryptamine 2 and neurokinin-1 receptor sites for quantitative ligand binding autoradiography. Only 5-hydroxytryptamine and neurokinin-1 sites were detected in the normal or serotonin/substance P-hyperinnervated inferior olivary complex. In the normal inferior olivary complex, the density of [ 3H]ketanserin binding (5-hydroxytryptamine, receptors) was relatively low, being the highest in pars a of the caudal medial accessory olive and the principal olive; moderate in pars c of the caudal medial accessory olive; truly low in the medial and the lateral dorsal accessory olive, nucleus b and pars b of the caudal medial accessory olive; and negligible in the middle medial accessory olive, rostral medial accessory olive and the smaller subnuclei. [ 125I]Bolton-Hunter-substance P binding (neurokinin-1 receptors) appeared denser, being highest in nucleus β and the middle medial dorsal accessory olive; moderate in the three portions of the caudal medial accessory olive, the lateral dorsal accessory olive and the dorsal cap of Kooy; low in the rostral medial accessory olive, the ventrolateral outgrowth and the dorsomedial cell column; and very low or null in the principal olive and the medial dorsal accessory olive. After serotonin/substance P hyperinnervation, there were striking increases in the apparent density of both populations of receptor. [ 3H]Ketanserin binding was now stronger in the most olivary subnuclei, including some in which it had not been found in the normal, such as the middle and the rostral medial accessory olive. [ 125I]Bolton-Hunter-substance P binding showed even greater elevations in a few subnuclei, such as the principal olive and the dorsomedial cell column; it was now detectable in the medial dorsal accessory olive, unchanged in the dorsal cap of Kooy and the ventrolateral outgrowth and slightly decreased in the lateral dorsal accessory olive. The normal and altered distributions of both ligands did not match the respective patterns of serotonin and substance P innervation and hyperinnervation previously demonstrated with immunocytochemistry. In some sectors of the inferior olivary complex where both transmitters are presumably co-localized, there was no overlap in the distribution of the respective binding sites either in the normal or in the hyperinnervated state. In view of current information on the cellular localization of 5-hydroxytryptamine 2 and neurokinin-1 receptors in brain, it seems likely that their increases in the hyperinnervated inferior olivary complex were largely the result of an up-regulation and not the mere reflection of an augmented number as autoreceptors on serotonin and/or substance P terminals.