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

Abstract

In forced-swim tests in mice and rats, the novel D 3 /D 2 receptor agonist S32504 [(ϩ)-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 [(Ϫ)-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)-4,2Ј-(1Ј,2Ј,3Ј,4Ј-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 Although the most familiar feature of Parkinson's disease is a disruption of motor function, it is accompanied by mood, sensory, and cognitive symptoms (Giladi et al., 2000). These often anticipate onset of frank motor dysfunction and are, in general, poorly treated by the prototypical antiparkinsonian agent L-3,4-dihydroxyphenylalanine (Giladi et al., 2000;Rascol et al., 2003). A perturbation of adrenergic, serotonergic, and cholinergic transmission likely contributes to these interrelated features of Parkinson's disease, but the principal underlying deficit is a degeneration of nigrostriatal dopaminergic projections together with a (less pronounced) dysfunction of mesolimbic and mesocortical dopaminergic pathways (Rascol et al., 2003). Interestingly, as indicated by the following observations, a disruption of dopaminergic transmission is implicated in the depressed mood displayed both by ParArticle, publication date, and citation information can be found at

Behavioral Actions of Intranasal Application of Dopamine: Effects on Forced Swimming, Elevated Plus-Maze and Open Field Parameters

“…The behavioral profile found for intra-nasally applied DA resembles those found for other antiparkinsonian agents [26,71] . Since, treatment with L -DOPA, the mainstay of therapy in Parkinson's disease, is accompanied by a number of side effects [83] , the intra-nasal delivery of exogenous DA into the brain may provide an alternative or adjunct in the therapy of diseases involving dopaminergic deficiencies.…”

“…Furthermore, it was shown that mixed D 2/3 -agonists suppressed immobility in the FST, which could be dissociated from its action on motor activity in a novel environment [67][68][69] . Likewise, other mixed DA-receptor agonists all exert antidepressant-like effects in experimental models of depression at doses that do not stimulate motor activity in unfamiliar environments and which, additionally, failed to influence anxiety-like behavior in the elevated plus-maze [26,70,71] . This is in accordance with the results from the elevated-plus maze of the present study.…”

“…Previous studies have shown a reduced level of the DA metabolite homovanillic acid in the cerebrospinal fluid in depressed patients [22][23][24] . Furthermore, D2 or mixed D2/D3 receptor agonists exert antidepressant-like effects in diverse depression models [25,26] and appear to be effective in treatment-resistant depressed patients [27][28][29] . Levels of DA declined in the nucleus accumbens after exposure to the forced swimming test (FST) [30] .…”

WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one]: A Novel Dopamine D2 Receptor Partial Agonist/Serotonin Reuptake Inhibitor with Preclinical Antipsychotic-Like and Antidepressant-Like Activity

“…It may be that the D 2 receptor partial agonist properties of WS-50030 and aripiprazole are sufficient to demonstrate efficacy in this model. Millan et al (2004) have reported preclinical efficacy with the D 3 /D 2 receptor agonists ropinirole and S32504 in depression models such as the forced swim test, learned helplessness, and chronic mild stress models that were blocked by D 2 but not D 3 receptor antagonists.…”

Disruption of the US pre-exposure effect and latent inhibition in two-way active avoidance by systemic amphetamine in C57BL/6 mice

“…Instead, the learned helplessness procedure has been widely used for the screening of antidepressant drugs (for a review, see Maier 1984;Willner 1984;Vollmayr and Henn 2001;Cryan et al 2002). Notably, a critical role of central dopamine in the control and modulation of inescapable shock-induced escape deficits in the learned helplessness paradigm has been identified (Muscat et al 1992;Besson et al 1998Besson et al , 1999Takamori et al 2001;Kram et al 2002;Millan et al 2004). Specifically, it has been demonstrated that the reversal of shock-induced deficits in avoidance and/or escape learning is associated with an increase in the functional responsiveness of central dopaminergic systems (Besson et al 1998;Takamori et al 2001).…”