INVITRO AND INVIVO DISPOSITION OF METHIOTHEPIN-H-3 IN BRAIN-TISSUES - RELATIONSHIP TO THE EFFECTS OF ACUTE TREATMENT WITH METHIOTHEPIN ON CENTRAL SEROTONINERGIC RECEPTORS

A single treatment with a large dose of methiothepin (20 mg/kg, i.p.) induced, as early as the 2nd day after injection, a significant increase (+20-35%) in the number of specific binding sites for 3H-5-HT in forebrain areas, particularly the hippocampus. Experiments with 3H-methiothepin indicated that the drug remained firmly bound to brain membranes thus maintaining a local concentration high enough to effectively block 5-HT receptors for 10-12 h after its peripheral administration. Accordingly, it can be concluded that the occupancy of central 5-HT receptor sites by methiothepin for several hours was sufficient to induce a supersensitivity phenomenon within the two following days. Although 3H-methiothepin was a useful marker for analyzing the disposition and the kinetics of the 5-HT antagonist in brain tissues, it could not be used as a specific ligand of 5-HT receptors in brain since under in vitro as well as in vivo conditions most of 3H-methiothepin bound to non-specific sites, especially to the lipid component of the membranes. © 1979 Springer-Verlag.