Novel sigma (sigma) receptor agonists produce antidepressant-like effects in mice

Abstract

Many antidepressant drugs interact with sigma receptors and accumulating evidence suggests that these proteins mediate antidepressant-like effects in animals and humans. sigma Receptors are localized in brain regions affected in depression, further strengthening the hypothesis that they represent logical drug development targets. In this study, two novel sigma receptor agonists (UMB23, UMB82) were evaluated for antidepressant-like activity in mice. First, radioligand binding studies confirmed that the novel compounds had preferential affinity for sigma receptors. Second, the forced swim test, a well established animal model for screening potential antidepressant drugs, showed that both compounds dose-dependently reduced immobility time. The sigma receptor antagonist BD1047 attenuated the antidepressant-like effects of UMB23 and UMB82. Third, locomotor activity suggested that the effects of UMB23 and UMB82 in the forced swim test were not due to non-specific motor activating effects. Together, the data provide further evidence that sigma receptor agonists represent a possible new class of antidepressant medication.

Figure 1

Structures of the novel σ receptor ligands: UMB23 (1-(3-phenylpropyl)piperidine oxalate) and UMB82 (2-(3,4-dichlorophenyl)-N-ethyl-N-(2-piperidin-1-ylethyl)ethanamine oxalate).

Figure 2

Antidepressant-like effects of desipramine (10-20 mg/kg, i.p.) and fluvoxamine (0.1-10 mg/kg, i.p.) in the mouse forced swim test. The tests started 30 min after the injection of saline or drugs. Data are expressed as mean ± S.E.M. (N=5-10/group). *P<0.05, **P<0.01.

Figure 3

Antidepressant-like effects of DTG (5-10 mg/kg, i.p) in the mouse forced swim test. The tests started 30 min after the injection of saline or drug. Data are expressed as mean ± S.E.M. (N=7-10/group). *P<0.05.

Figure 4

Antidepressant-like effects of UMB23 (2.5-20 mg/kg, i.p.) and UMB82 (10-40 mg/kg, i.p.) in the mouse forced swim test. The tests started 30 min after the injection of saline or drugs. Data are expressed as mean ± S.E.M. (N=5-10/group). **P<0.01.

Figure 5

Antidepressant-like effects of BD1047 (5 mg/kg, i.p.) + UMB23 (20 mg/kg, i.p.) and BD1047 (5 mg/kg, i.p.) + UMB82 (40 mg/kg, i.p.) in the mouse forced swim test. The mice were injected with saline or drugs 15 min after the BD1047 pretreatment. The tests started 15 min after the injection of saline or drugs. Data are expressed as mean ± S.E.M. (N=10/group). *P<0.05, **P<0.01.

Figure 6

Locomotor activity of desipramine (10-20 mg/kg, i.p.), fluvoxamine (1-10 mg/kg, i.p.) and DTG (5-10 mg/kg, i.p.). Data was evaluated during the 4 min corresponding to the data collection period of the forced swim tests. Data are expressed as mean ± S.E.M. (N=8/group). **P<0.01.

Figure 6

Locomotor activity of desipramine (10-20 mg/kg, i.p.), fluvoxamine (1-10 mg/kg, i.p.) and DTG (5-10 mg/kg, i.p.). Data was evaluated during the 4 min corresponding to the data collection period of the forced swim tests. Data are expressed as mean ± S.E.M. (N=8/group). **P<0.01.

Figure 7

Locomotor activity of UMB23 (5-20 mg/kg, i.p.) and UMB82 (20-40 mg/kg, i.p.). Data was evaluated during the 4 min corresponding to the data collection period of the forced swim tests. Data are expressed as mean ± S.E.M. (N=7-8/group). *P<0.05, **P<0.01.