The CRF1 receptor antagonist, DMP695, abolishes activation of locus coeruleus noradrenergic neurones by CRF in anesthetized rats.
Corticotropin-releasing factor (CRF)(1) receptors have been implicated in the excitatory influence of CRF upon noradrenergic perikarya of the locus coeruleus. This study thus characterized the influence of the novel CRF(1) receptor antagonist, DMP695 (N-(2-chloro-4,6-dimethylphenyl)-1-[1-methoxymethyl-(2-methoxyethyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine mesylate), upon the electrical activity of noradrenergic perikarya in the locus coeruleus of anesthetized rats. Intracerebroventricular injection of CRF dose-dependently (0.05-4.0 microg) enhanced the firing rate of noradrenergic cell bodies and transformed their firing pattern into a burst mode. This action was dose-dependently abolished by i.v. administration of DMP695 (0.125-2.0 mg/kg i.v.), which did not itself modify the electrical activity of noradrenergic neurones. These data demonstrate antagonist properties of DMP695 at central CRF(1) receptors excitatory to ascending noradrenergic neurones, an action which may contribute to its distinctive profile of anxiolytic properties.
Lejeune
Françoise
F
Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 Chemin de Ronde, 78290 Croissy/Seine, Paris, France.
Millan
Mark J
MJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D003000:Clonidine / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D007276:Injections, Intraventricular; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000099052:CRF Receptor, Type 1
C437952:(N-(2-chloro-4,6-dimethylphenyl)-1-(1-methoxymethyl)-(2-methoxymethyl)-6-methyl-1H-1,2,3-triazolo(4,5-c)pyridin-4-amine) mesylate; D000316:Adrenergic alpha-Agonists; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D003000:Clonidine; D009638:Norepinephrine