Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species.
BACKGROUND
Previous studies have demonstrated behaviors indicative of anxiolysis in rats pretreated with the nociceptin receptor (opioid receptor like-1, ORL-1) agonist, Ro64-6198.


OBJECTIVE
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.
Varty
G B
GB
Department of Neurobiology, K-15-2600, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Geoffrey.Varty@SPCorp.com
Hyde
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Hodgson
R A
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Lu
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McCool
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Kazdoba
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Del Vecchio
R A
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Guthrie
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Pond
A J
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Grzelak
M E
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Xu
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Korfmacher
W A
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Tulshian
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Parker
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Higgins
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D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000633:toxicity; D001143:Arousal / Q000187:drug effects*; D001562:Benzimidazoles / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009292:Narcotic Antagonists; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists*; D013045:Species Specificity; D013141:Spiro Compounds / Q000494:pharmacology* / Q000633:toxicity; D014828:Vocalization, Animal / Q000187:drug effects; D000094942:Nociceptin Receptor
D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D007093:Imidazoles; C402921:J 113397; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C408068:Ro 64-6198; D013141:Spiro Compounds; D002707:Chlordiazepoxide; D000094942:Nociceptin Receptor