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Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species

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Abstract

Rationale

Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198.

Objectives

The aim of this study was to examine the effects of Ro64-6198 in anxiety models across three species: rat, guinea pig, and mouse. In addition, the receptor specificity of Ro64-6198 was studied, using the ORL-1 receptor antagonist, J-113397, and ORL-1 receptor knockout (KO) mice. Finally, neurological studies examined potential side effects of Ro64-6198 in the rat and mouse.

Results

Ro64-6198 (3–10 mg/kg) increased punished responding in a rat conditioned lick suppression test similarly to chlordiazepoxide (6 mg/kg). This effect of Ro64-6198 was attenuated by J-113397 (10 mg/kg), but not the mu opioid antagonist, naltrexone (3 mg/kg). In addition, Ro64-6198 (1–3 mg/kg) reduced isolation-induced vocalizations in rat and guinea pig pups. Ro64-6198 (3 mg/kg) increased the proportion of punished responding in a mouse Geller–Seifter test in wild-type (WT) but not ORL-1 KO mice, whereas diazepam (1–5.6 mg/kg) was effective in both genotypes. In rats, Ro64-6198 reduced locomotor activity (LMA) and body temperature and impaired rotarod, beam walking, and fixed-ratio (FR) performance at doses of 10–30 mg/kg, i.e., three to ten times higher than an anxiolytic dose. In WT mice, Ro64-6198 (3–10 mg/kg) reduced LMA and rotarod performance, body temperature, and FR responding, but these same measures were unaffected in ORL-1 KO mice. Haloperidol (0.3–3 mg/kg) reduced these measures to a similar extent in both genotypes. These studies confirm the potent, ORL-1 receptor-mediated, anxiolytic-like effects of Ro64-6198, extending the findings across three species. Ro64-6198 has target-based side effects, although the magnitude of these effects varies across species.

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Authors and Affiliations

  1. Department of Neurobiology, K-15-2600, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ, 07033, USA

    G. B. Varty, L. A. Hyde, R. A. Hodgson, S. X. Lu, M. F. McCool, T. M. Kazdoba, R. A. Del Vecchio, D. H. Guthrie, A. J. Pond, M. E. Grzelak, E. M. Parker & G. A. Higgins

  2. Department of Exploratory Drug Metabolism, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ, 07033, USA

    X. Xu & W. A. Korfmacher

  3. Department of Medicinal Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ, 07033, USA

    D. Tulshian

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  1. G. B. Varty
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  2. L. A. Hyde
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  3. R. A. Hodgson
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  4. S. X. Lu
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  6. T. M. Kazdoba
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  7. R. A. Del Vecchio
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  10. M. E. Grzelak
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  11. X. Xu
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  13. D. Tulshian
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  14. E. M. Parker
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  15. G. A. Higgins
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Correspondence to G. B. Varty.

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Varty, G.B., Hyde, L.A., Hodgson, R.A. et al. Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species. Psychopharmacology 182, 132–143 (2005). https://doi.org/10.1007/s00213-005-0041-4

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  • DOI: https://doi.org/10.1007/s00213-005-0041-4

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