Characterization of the V1a antagonist, JNJ-17308616, in rodent models of anxiety-like behavior
Abstract
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.
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V1A and V1B receptor antagonists have demonstrated anxiolytic and antidepressant effects in preclinical studies.
“Indeed, V 1A and V 1B receptor antagonists have demonstrated anxiolytic and antidepressant effects in preclinical studies (Bleickardt et al., 2009;Hodgson et al., 2014).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Bleickardt et al., 2009
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- 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.
- Corresponding author
- Hodgson, R. A.
- Venue
- Psychopharmacology
- Published
- 2008-10-16
- Volume
- 202
- Issue
- 4
- Pages
- 711-718
- ISSN
- 0033-3158 (ISSN-L)
- 1432-2072
- OpenAlex
- W1984540432
- Cited by
- 71
- References
- 16
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- FWCI
- 5.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Psychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- vasopressin V1a receptor, vasopressin, anxiety-like behavior, anxiolytics, elevated plus maze, marble burying, social recognition, locomotor activity
- MeSH terms
- Animals, Anxiety, Arginine Vasopressin, Behavior, Animal, Conditioning, Operant, Dose-Response Relationship, Drug, Female, Male, Motor Activity, Ovariectomy, Social Behavior, Spiro Compounds, Anti-Anxiety Agents, Vasopressins, Vocalization, Animal, Rats, Sprague-Dawley, Receptors, Vasopressin, Mice, Knockout, Recognition, Psychology, Mice, Rats, Antidiuretic Hormone Receptor Antagonists
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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