title: Paradoxical decrease of brain 5-HT turnover by metergoline, a central 5-HT receptor blocker.
abstract: Since metergoline (1-methyl-8-beta-carbobenzyloxy-aminomethyl-10-alpha-ergoline) is a potent 5-HT antagonist in peripheral organs, its possible blocking effects on 5-HT receptors in the rat brain were investigated. In vitro, metergoline inhibited both the specific high affinity binding of 3-H-5-HT onto synaptosomal membranes (IC 50 = 18 nM) and the stimulating effect of 10 micron 5-HT on the adenylate cyclase activity in colliculi homogenates from newborn rats (IC 50 = 12 micron. In vivo, the administration of metergoline (10 mg/kg i.p., 60 min before death) resulted in a significant decrease in the 3-H-5-HT binding capacity of synaptosomal membranes from the forebrain of adult rats. Taken together, these data clearly indicated that metergoline is a potent blocker of some serotoninergic receptors in the rat brain. Surprisingly, the changes in 5-HT turnover occurring in the brainstem and in the forebrain 1 h after metergoline (2-10 mg/kg) treatment were similar to those normally induced by a central 5-HT agonist: both the rate of 5-HT utilisation and that of 5-HT synthesis were significantly decreased. These changes were in contrast to the acceleration of 5-HT turnover induced by the administration of another potent central 5-HT antagonist, methiothepin. These results are discussed in relation to the possible existence of several types of serotoninergic receptors in the rat brain. It is possible that the positive feedback regulation of 5-HT turnover is triggered by the blockade of serotoninergic receptors sensitive to methiothepin, but not to metergoline.
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004873:Ergolines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000096:biosynthesis; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000378:metabolism; D008711:Metergoline / Q000494:pharmacology*; D008719:Methiothepin / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism*; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D004873:Ergolines; D007211:Indoles; D011985:Receptors, Serotonin; D008711:Metergoline; D012701:Serotonin; D008719:Methiothepin; D008238:Lysergic Acid Diethylamide; D000262:Adenylyl Cyclases; D011188:Potassium