Further studies on the mechanism of serotonin-dependent anorexia in rats.
4-(3-Indolyl-2-ethyl) piperidine (LM 5008), 2-(1-piperazinyl) quinoline (quipazine), and metachlorophenylpiperazine (mCPP) were studied for their ability to affect serotonergic mechanisms in vitro. Their relative potency in inhibiting serotonin (5-HT) uptake in vivo and reducing food intake in rats was also examined. mCPP was very potent in displacing 3H-5-HT bound to brain membranes (IC50, 6.2 X 10(-7) M), followed by quipazine, which showed an IC50 of 3.8 X 10(-6) M. LM 5008 was the least effective with an IC50 of 3.6 X 10(-5) M. mCPP and quipazine were less potent than d-fenfluramine in releasing 14C-5-HT from brain synaptosomes, while LM 5008 caused no significant effects at a concentration of 10(-5) M. Conversely, both in vitro and in vivo studies on 5-HT uptake showed that LM 5008 was the most potent compound in inhibiting 5-HT uptake and mCPP the least potent. Since a 50% reduction of food intake was not reached even with a dose of LM 5008 27-times higher than the ED50 for inhibiting 5-HT uptake in vivo, it is suggested that even marked inhibition of 5-HT uptake at central synapses is not sufficient per se to trigger serotonin-dependent anorexia in the rat. Increased release and/or direct stimulation of post-synaptic receptors may be necessary to obtain this effect. This could be of interest for developing new agents which can cause anorexia by interacting with brain serotonin.
D000818:Animals; D000855:Anorexia / Q000503:physiopathology*; D001921:Brain / Q000648:ultrastructure; D005247:Feeding Behavior / Q000187:drug effects; D001068:Feeding and Eating Disorders / Q000503:physiopathology*; D005260:Female; D005277:Fenfluramine / Q000494:pharmacology; D006801:Humans; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011814:Quipazine / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors
D010879:Piperazines; D010880:Piperidines; D012702:Serotonin Antagonists; D005277:Fenfluramine; D012701:Serotonin; D011814:Quipazine; C015068:1-(3-chlorophenyl)piperazine; C018181:indalpine