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NEUROPHARMACOLOGY

S32504, a Novel Naphtoxazine Agonist at Dopamine D₃/D₂ Receptors: III. Actions in Models of Potential Antidepressive and Anxiolytic Activity in Comparison with Ropinirole

Psychopharmacology Department (M.J.M., M.B., A.D.) and Chemistry B Department (J.-L.P.), Institut de Recherches Servier, Paris, France; Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland (M.P.); Biotrial, Rue Jean-Louis Bertrand, 35000 Rennes, France (C.D.L.R.); and University Department of Pharmacology, Oxford, United Kingdom (F.S., T.S.)

In forced-swim tests in mice and rats, the novel D₃/D₂ receptor agonist S32504 [(+)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth[1,2-b]-1,4-oxazine] dose-dependently (0.04–2.5 mg/kg) and stereospecifically suppressed immobility compared with its enantiomer S32601 [(-)-trans-3,4,4a,5,6,10b-hexahydro-9-carbamoyl-4-propyl-2H-naphth-[1,2-b]-1,4-oxazine]. Ropinirole was less potent than S32504 in this procedure, and it was likewise less potent than S32504 (0.04–2.5 mg/kg) in attenuating motor-suppressant properties of the ₂-adrenoceptor agonist S18616 [(S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(1',2',3',4'-tetrahydronaphthalene)]]. In a learned helplessness paradigm, S32504 (0.08–2.5 mg/kg) suppressed escape failures. Furthermore, in a chronic mild stress model of anhedonia, S32504 (0.16–2.5 mg/kg) rapidly restored the suppression of sucrose consumption. S32504 inhibited marble-burying behavior in mice (0.04–0.16 mg/kg) and aggressive behavior in isolated mice (0.04–2.5 mg/kg): only higher doses of ropinirole mimicked these actions of S32504. In tests of anxiolytic activity, S32504 was more potent (0.0025–0.16 mg/kg) than ropinirole in suppressing fear-induced ultrasonic vocalizations, and S32601 was inactive. Furthermore, in contrast to ropinirole, S32504 modestly enhanced punished responses in a Vogel conflict procedure and increased open-arm entries in a plus-maze. At doses active in the above-described procedures, S32504 did not elicit hyperlocomotion. In the forced-swim, marble-burying, and ultrasonic vocalization models, actions of S32504 were blocked by the D₂/D₃ antagonists haloperidol and raclopride and by the D₂ antagonist L741,626 [4-(4-chlorophenyl)-1-(1H-indol-3-ylmethyl)piperidin-4-ol], but not by the D₃ receptor antagonist S33084 [(3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl)benzamide. Finally, chronic administration of S32504 did not, in contrast to venlafaxine, modify corticolimbic levels of serotonin_2A receptors or brain-derived neurotrophic factor. In conclusion, S32504 displays a broad and distinctive profile of activity in models of potential antidepressive and anxiolytic properties. Its actions are more pronounced than those of ropinirole and principally involve engagement of D₂ receptors.

Address correspondence to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, 125 chemin de Ronde, 78290 Croissy/Seine, France. E-mail: mark.millan{at}fr.netgrs.com

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				M. J. Millan, D. Cussac, A. Gobert, F. Lejeune, J.-M. Rivet, C. M. La Cour, A. Newman-Tancredi, and J.-L. Peglion S32504, a Novel Naphtoxazine Agonist at Dopamine D3/D2 Receptors: I. Cellular, Electrophysiological, and Neurochemical Profile in Comparison with Ropinirole J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 903 - 920. [Abstract] [Full Text] [PDF]

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