Pharmacological characterization of the receptor mediating the anorexigenic action of the octadecaneuropeptide: evidence for an endozepinergic tone regulating food intake.
Peptides of the endozepine family, including diazepam-binding inhibitor, the triakontatetraneuropeptide, and the octadecaneuropeptide (ODN), act through three types of receptors, that is, central-type benzodiazepine receptors (CBR), peripheral-type (mitochondrial) benzodiazepine receptors (PBR) and a metabotropic receptor positively coupled to phospholipase C via a pertussis toxin-sensitive G protein. We have previously reported that ODN exerts a potent anorexigenic effect in rat and we have found that the action of ODN is not affected by the mixed CBR/PBR agonist diazepam. In the present report, we have tested the possible involvement of the metabotropic receptor in the anorexigenic activity of ODN. Intracerebroventricular administration of the C-terminal octapeptide (OP) and its head-to-tail cyclic analog cyclo(1-8)OP (cOP) at a dose of 100 ng mimicked the inhibitory effect of ODN on food intake in food-deprived mice. The specific CBR antagonist flumazenil and the PBR antagonist PK11195 did not prevent the effect of ODN, OP, and cOP on food consumption. In contrast, the selective metabotropic endozepine receptor antagonist cyclo(1-8)[DLeu(5)]OP (100-1000 ng; cDLOP) suppressed the anorexigenic effect of ODN, OP, and cOP. At the highest concentration tested (1000 ng), cDLOP provoked by itself a significant increase in food intake. Taken together, the present results indicate that the anorexigenic effect of ODN and OP is mediated through activation of the metabotropic receptor recently characterized in astrocytes. The data also suggest that endogenous ODN, acting via this receptor, exerts an inhibitory tone on feeding behavior.
do Rego
Jean-Claude
JC
CNRS FRE 2735, Laboratory of Experimental Neuropsychopharmacology, European Institute for Peptide Research IFRMP 23, Faculty of Medicine and Pharmacy, University of Rouen, Rouen Cedex, France. jean-claude.dorego@univ-rouen.fr
Orta
Marie-Hélène
MH
Leprince
Jérôme
J
Tonon
Marie-Christine
MC
Vaudry
Hubert
H
Costentin
Jean
J
D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D001066:Appetite / Q000187:drug effects / Q000502:physiology*; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology*; D026261:Diazepam Binding Inhibitor / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005442:Flumazenil / Q000494:pharmacology; D005508:Food Deprivation / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D007031:Hypothalamus / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D010446:Peptide Fragments / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000187:drug effects / Q000378:metabolism*
D026261:Diazepam Binding Inhibitor; D018757:GABA Modulators; D058787:GABA-A Receptor Antagonists; D007546:Isoquinolines; D009479:Neuropeptides; D010446:Peptide Fragments; D010455:Peptides; D043562:Receptors, G-Protein-Coupled; D011963:Receptors, GABA-A; D018013:Receptors, Neuropeptide; C067529:diazepam binding inhibitor (33-50); D005442:Flumazenil; C037850:PK 11195