Characterization of the V1a antagonist, JNJ-17308616, in rodent models of anxiety-like behavior

• Published in: Psychopharmacology 2009-03, Vol.202 (4), p.711-718
• Main Authors: Bleickardt, C. J., Mullins, D. E., MacSweeney, C. P., Werner, B. J., Pond, A. J., Guzzi, M. F., Martin, F. D. C., Varty, G. B., Hodgson, R. A.
• Format: Article
• Language: English
• Subjects: Animal behavior; Animals; Antagonist drugs; Anti-Anxiety Agents - pharmacology; Antidiuretic Hormone Receptor Antagonists; Anxiety; Anxiety - psychology; Arginine Vasopressin - pharmacology; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Conditioning, Operant - drug effects; Dose-Response Relationship, Drug; Female; Hormones; Male; Mice; Mice, Knockout; Motor Activity - drug effects; Neurosciences; Original Investigation; Ovariectomy; Pharmacology/Toxicology; Psychiatry; Psychopharmacology; Rats; Rats, Sprague-Dawley; Receptors, Vasopressin - genetics; Recognition (Psychology) - drug effects; Rodents; Social Behavior; Spiro Compounds - pharmacology; Vasopressins - metabolism; Vocalization, Animal - drug effects
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-008-1354-x

Rationale Vasopressin (AVP) plays a role in regulating anxiety, which is thought to be partially mediated through the V1a receptor. Recently, JNJ-17308616 was identified as a V1a antagonist. Objectives The purpose of this work was to assess V1a receptor affinity and selectivity of JNJ-17308616 and in vivo efficacy in animal models of anxiety-like behavior. Materials and methods The affinity of JNJ-17308616 for the human and rat V1a, V1b, V2, and oxytocin receptors was determined. Central administration of AVP induces a scratching response mediated through the V1a receptor. Inhibition of scratching was used as a behavioral measure of in vivo potency. JNJ-17308616 was tested in five models of anxiety: rat elevated plus-maze (EPM), rat-elevated zero-maze (EZM), rat-conditioned lick suppression (CLS), rat pup separation-induced ultrasonic vocalizations (USV), and mouse marble burying (MMB). Results High affinity for the human V1a receptor ( K i 5.0 nM) was confirmed. However, the rat V1a receptor affinity was more modest ( K i 216 nM), and the compound was not selective over the rat V2 receptor ( K i 276 nM). At 100 mg/kg, JNJ-17308616 significantly reduced anxiety-like behavior in EPM, USV, and MMB; at 30 mg/kg, it was effective in EZM and CLS. JNJ-17308616 neither impaired social recognition nor reduced locomotor activity. Conclusions These results demonstrate the potential for V1a receptor antagonists as novel anxiolytics. Tool compounds that have greater V1a receptor selectivity than JNJ-17308616 are necessary to make precise conclusions about the role of the V1a receptor in affective disorders.