title: Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species.
abstract: 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.
authors: Department of Neurobiology, K-15-2600, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Geoffrey.Varty@SPCorp.com
authors: G B
authors: GB
authors: Varty
authors: L A
authors: LA
authors: Hyde
authors: R A
authors: RA
authors: Hodgson
authors: S X
authors: SX
authors: Lu
authors: M F
authors: MF
authors: McCool
authors: T M
authors: TM
authors: Kazdoba
authors: R A
authors: RA
authors: Del Vecchio
authors: D H
authors: DH
authors: Guthrie
authors: A J
authors: AJ
authors: Pond
authors: M E
authors: ME
authors: Grzelak
authors: X
authors: X
authors: Xu
authors: W A
authors: WA
authors: Korfmacher
authors: D
authors: D
authors: Tulshian
authors: E M
authors: EM
authors: Parker
authors: G A
authors: GA
authors: Higgins
mesh_terms: 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
chemical_list: 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