In vitro and in vivo disposition of 3H-methiothepin 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.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003988:Dibenzothiepins / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000378:metabolism; D008719:Methiothepin / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000502:physiology; D013134:Spiperone / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors
D003988:Dibenzothiepins; D011985:Receptors, Serotonin; D012701:Serotonin; D013134:Spiperone; D008719:Methiothepin; D000262:Adenylyl Cyclases; D006220:Haloperidol