dizocilpine-maleate and Hyperphagia

The effects of the glutamate N-methyl-D-aspartate (NMDA) receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5, 10-imine (MK-801) on 2-deoxy-D-glucose-induced hyperphagia were investigated in rats. MK-801 significantly increased 2-deoxy-D-glucose-elicited eating. The facilitating effects of MK-801 on 2-deoxy-D-glucose-elicited feeding were not affected by coadministration of a nitric oxide (NO) precursor, L-arginine. Because NO synthase inhibitors inhibit 2-deoxy-D-glucose-induced hyperphagia and activation of the NMDA receptor leads to NO formation, our results suggest that blockade of the NMDA receptor increases 2-deoxy-D-glucose-induced hyperphagia, which is unrelated to inhibition of NO, and that NMDA receptors may play a role in satiety.

Topics: Animals; Arginine; Deoxyglucose; Dizocilpine Maleate; Drug Interactions; Eating; Excitatory Amino Acid Antagonists; Hyperphagia; Male; Rats; Rats, Sprague-Dawley

The effect of intracerebroventricular administration of dizocilpine on feeding behaviour and adrenal corticrotropic hormone (ACTH)-induced anorexia in elevated plus maze was examined. Dizocilpine (10, 20 and 40 nmol/rat, i.c.v.) showed a dose-dependent increase in food intake in 16 h food deprived rats. Dopamine receptor antagonists such as SCH 23390 (0.25 and 0.5 mg/kg, i.p.), pimozide (0.5 and 1 mg/kg, i.p.) and haloperidol (0.25 and 0.5 mg/kg, i.p.) dose-dependently blocked dizocilpine (40 nmol)-induced potentiation of food intake. Brain dopamine depletion by pretreatment with reserpine (5 mg/kg, i.p.) and alpha-methyl-p-tyrosine (200 mg/kg, i.p.) decreased food intake in rats. Similarly, pretreatment with reserpine and alpha-methyl-p-tyrosine (AMPT) reversed the hyperphagic effect of dizocilpine (20 and 40 nmol). Intracerebroventricular administration of ACTH (5 microgram/rat) produced significant diminution of feeding duration and increased tasting latency and feeding latency in elevated plus maze which was reversed by dizocilpine (40 nmol). SCH 23390 (0.25 mg/kg), pimozide (0.5 mg/kg) and haloperidol (0.25 mg/kg) reversed the effect of dizocilpine on ACTH-induced behaviours in elevated plus maze. The present observations support and extend the hypothesis that endogenous excitatory aminoacids (EAAs) play a role in the control of food intake. Further, dizocilpine-induced hyperphagia and dizocilpine-induced reversal of ACTH effect on feeding behaviour in elevated plus maze involve DAergic mediation.

Topics: Adrenocorticotropic Hormone; Animals; Dizocilpine Maleate; Dopamine Antagonists; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Feeding Behavior; Hyperphagia; Injections, Intraventricular; Male; Maze Learning; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate