Received for publication November 5, 2003.
Revised February 4, 2004.
Accepted for publication February 12, 2004.

S32504, a novel naphtoxazine agonist at dopamine D₃/D₂ receptors: III. Actions in models of potential antidepressive and anxiolytic activity in comparison to ropinirole

Abstract

In forced-swim tests in mice and rats, the novel D₃/D₂ receptor agonist, S32504, dose-dependently (0.04-2.5 mg/kg) and stereospecifically suppressed immobility as compared with its enantiomer, S32601. Ropinirole was less potent than S32504 in this procedure, and it was likewise less potent than S32504 (0.04-2.5) in attenuating motor-suppressant properties of the ₂-adrenoceptor agonist, S18616. In a learned helplessness paradigm, S32504 (0.08-2.5) suppressed escape failures. Further, in a chronic mild stress model of anhedonia, S32504 (0.16-2.5) rapidly restored the suppression of sucrose consumption. S32504 inhibited marble burying behaviour in mice (0.04-0.16) and aggressive behaviour in isolated mice (0.04-2.5): only higher doses of ropinirole mimicked these actions of S32504. In tests of anxiolytic activity, S32504 was more potent (0.0025-0.16) than ropinirole in suppressing fear-induced ultrasonic vocalizations, and S32601 was inactive. Further, 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, but not by the D₃ receptor antagonist, S33084. 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

Key words: D2 receptor, D3 receptor, antidepressant, anxiety, anxiolytic, depression

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