d-Fenfluramine- and d-norfenfluramine-induced hypophagia: differential mechanisms and involvement of postsynaptic 5-HT receptors.
Severe depletion of 5-hydroxytryptamine (5-HT) by para-chlorophenylalanine (pCPA, 150 mg/kg per day x3) did not alter the hypophagic effect of d-fenfluramine (1-3 mg/kg i.p.) 1 h after food presentation in 24-h food-deprived rats, and moderately and comparably increased the hypophagic effects of its metabolite, d-norfenfluramine (0.35-1.0 mg/kg i.p.), and of the 5-HT1C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP; 1.5, 2.0 mg/kg i.p.). Chronic treatment with mCPP (2.5 mg/kg i.p. x 14) attenuated the hypophagia induced by d-norfenfluramine (1, 1.5 mg/kg) but not d-fenfluramine (1, 3 mg/kg). 1-(1-Naphthyl)piperazine (3, 8 mumol/kg s.c.), which has greater affinity for 5-HT1C than for 5-HT2 receptors, had no effect on the hypophagia induced by d-fenfluramine (1.25, 2.0 mg/kg), but 1.3 and 3 mumol/kg 1-(1-naphthyl)piperazine largely and comparably attenuated the substantial hypophagic effect of d-norfenfluramine (0.75 mg/kg). The essentially complete hypophagic action of d-norfenfluramine (1.25 mg/kg) was inhibited by 1-(1-naphthyl)piperazine with ID50 = 2.13 mumol/kg. Ketanserin, which binds more weakly than 1-(1-naphthyl)piperazine to 5-HT1C receptors and more strongly to 5-HT2 receptors, attenuated weaker but not stronger hypophagic effects of d-fenfluramine (1.25, 2.0 mg/kg) when given at high dosage (8, 16 mumol/kg s.c.). Ketanserin (16 mumol/kg) also weakly attenuated the hypophagia due to d-norfenfluramine (0.75 mg/kg), but not the essentially complete hypophagia due to d-norfenfluramine (1.25 mg/kg).(ABSTRACT TRUNCATED AT 250 WORDS)
Gibson
E L
EL
Department of Neurochemistry, Institute of Neurology, London, UK.
Kennedy
A J
AJ
Curzon
G
G
D000818:Animals; D004347:Drug Interactions; D001068:Feeding and Eating Disorders / Q000139:chemically induced*; D010134:Fenclonine / Q000494:pharmacology; D005277:Fenfluramine / Q000633:toxicity*; D008297:Male; D009642:Norfenfluramine / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D009642:Norfenfluramine; D005277:Fenfluramine; D010134:Fenclonine; C015068:1-(3-chlorophenyl)piperazine