Abstract

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 α₂-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.