The octadecaneuropeptide ODN induces anxiety in rodents: possible involvement of a shorter biologically active fragment.
The octadecaneuropeptide ODN has been originally characterized as an endogenous ligand of central-type benzodiazepine receptors, on its ability to displace the anxiogenic compound beta-[3H]carboline-3-carboxylate methyl ester from its binding sites. The aim of the present study was to investigate the anxiogenic effects of intracerebroventricular administration of ODN in mice and rats. At doses ranging from 10 to 100 ng, ODN increased in mice the latency to explore a white compartment when the animals were placed in a black one. ODN also reduced the first stay duration in the white compartment. These effects were antagonized by diazepam (0.075 mg/kg, s.c.) as well as flumazenil (1 mg/kg, s.c.), indicating that ODN acts as an inverse agonist on central-type benzodiazepine receptors. In rats, ODN reduced the latency to enter a black compartment when the animals were placed in the white one. In the plus-maze elevated test, ODN reduced, in both mice and rats, the number of entries and the time spent in the open arm. In mice, ODN (100 ng) increased the thigmotaxis index, i.e. the distance traveled in the peripheral zone of the open field. Time-course studies revealed that a significant effect of ODN (100 ng) in the black/white compartment test was only observed 40 min after the injection and lasted between 3 and 6 h. The effect of a 1000-ng dose of ODN appeared more tardily than that of a 10-ng dose. In addition, a 1000-ng dose of ODN occluded the early effect of a 100-ng dose on the white compartment first stay duration. The COOH-terminal octapeptide of ODN was more rapidly effective than ODN in the black/white compartment test, suggesting that the anxiogenic effect of the peptide requires the formation of biologically active proteolytic fragment.
De Mateos-Verchere
J G
JG
Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (no. 23), Unité de Neuropsychopharmacologie, CNRS UPRES-A 6036, Faculté de Médecine et Pharmacie de Rouen, Saint-Etienne du Rouvray, France.
Leprince
J
J
Tonon
M C
MC
Vaudry
H
H
Costentin
J
J
D000595:Amino Acid Sequence; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001007:Anxiety / Q000139:chemically induced*; D003975:Diazepam / Q000494:pharmacology; D026261:Diazepam Binding Inhibitor; D004193:Discrimination Learning / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects*; D005442:Flumazenil / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
D014151:Anti-Anxiety Agents; D026261:Diazepam Binding Inhibitor; D009479:Neuropeptides; D010446:Peptide Fragments; C067529:diazepam binding inhibitor (33-50); D005442:Flumazenil; D003975:Diazepam