The distribution of 5-HT(6) receptors in rat brain: an autoradiographic binding study using the radiolabelled 5-HT(6) receptor antagonist [(125)I]SB-258585.

We used the highly selective 5-HT(6) receptor radioligand [(125)I]SB-258585 (4-iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide) to perform autoradiographic binding studies on the rat brain. High levels of specific binding occurred in the corpus striatum, nucleus accumbens, Islands of Calleja and the olfactory tubercle. A high level of binding also appeared in the choroid plexus. Moderate levels occurred in several regions of the hippocampal formation and in certain regions of the cerebral cortex, thalamus, hypothalamus, and substantia nigra; and very low levels in the globus pallidus, cerebellum, other mesencephalic regions, and the rhombencephalon. Displacement of total binding with 10 microM unlabelled SB-214111 (4-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzene-sulfonamide), another selective 5-HT(6) receptor antagonist, or 10 microM unlabelled methiothepin, reduced binding to barely discernible levels. Some animals received unilateral injections of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle to lesion the nigro-striatal pathway before autoradiographic examination. Effectiveness of the 6-OHDA lesions in the substantia nigra and striatum was confirmed with tyrosine hydroxylase immunohistochemistry. Such lesions resulted in no significant changes in [(125)I]SB-SB258585 binding in any brain region examined, suggesting that 5-HT(6) receptors in the striatum are not located on dendritic, somatic or terminal elements of dopaminergic neurones. Thus, the striatal binding sites seen in this study may be on intrinsic GABAergic or cholinergic neurones, or on terminals of projection neurones from the thalamus or cerebral cortex. The 5-HT(6) receptor ligand binding seen here in the striatum, accumbens, olfactory tubercle, Islands of Calleja, cerebral cortex and hippocampus are in concordance with previous immunohistochemical studies, and suggest a possible involvement of 5-HT(6) receptors in locomotor control, cognition, memory, and control of affect. The high levels of binding observed in the choroid plexus in this study have not been reported before. This finding suggests that 5-HT(6) receptors could play a role in the control of cerebrospinal fluid dynamics.