Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models

Abstract

Aim: To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice.

Methods: In the learned helplessness test (LH), Neu-P11 or melatonin (25-100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25-100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25-100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed.

Results: In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon.

Conclusion: The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models.

Figure 1

Effects of Neu-P11 on the number of escape failures (A) and intertrial crossings (B) over the 3 days of testing in the learned helplessness model in rats. Neu-P11 (25, 50, or 100 mg/kg) and imipramine (32 mg/kg) were injected repeatedly on 5 consecutive days as described in the methods section. Escape tests were performed on day 3−5. ^bP<0.05, ^cP<0.01 vs the helpless control rats. NHC, non-helpless control; HC, helpless control; Imip, imipramine.

Figure 2

Effects of melatonin on the number of escape failures (A) and intertrial crossings (B) over the 3 days of testing in the learned helplessness model in rats. Melatonin (25, 50, and 100 mg/kg) and imipramine (32 mg/kg) were injected repeatedly on 5 consecutive days as described in the methods section. Escape tests were performed on day 3–5. ^bP<0.05, ^cP<0.01 vs the helpless control rats. NHC, non-helpless control; HC, helpless control; Imip, imipramine.

Figure 3

Effects of a single drug administration on the immobility time of rats in the forced swimming test. Neu-P11 (25, 50, and 100 mg/kg) and imipramine (32 mg/kg) were injected 2 h (A) or 12 h (B) before test phase, respectively. ^bP<0.05, ^cP<0.01 vs vehicle-treated rats. Veh, vehicle; Imip, imipramine.

Figure 4

Effects of a repeated drug administration on the immobility time of rats in the forced swimming test. Neu-P11 (25, 50, and 100 mg/kg) and imipramine (32 mg/kg) were injected repeatedly on 6 consecutive days (once per day), and the test was performed on day 7. ^cP<0.01 vs vehicle-treated rats. Veh, vehicle; Imip, imipramine.

Figure 5

Dose-effects of a single drug administration on the percentage of time spent in the open arms (A), the percentage of the open arms entries (B) and the number of the closed arms entries (C) in the elevated plus-maze model in mice. Neu-P11 (25, 50, and 100 mg/kg) and diazepam (2 mg/kg) were injected 2 h prior to a 5 min test. ^bP<0.05, ^cP<0.01 vs vehicle-treated mice. Veh, vehicle; Dia, diazepam.

Figure 6

Time-effects of a single administration on the percentage of time spent in the open arms (A), the percentage of the open arms entries (B) and the number of the closed arms entries (C) in the elevated plus-maze model in mice. Neu-P11 (50 mg/kg) was injected 0.5 h, 1 h, 2 h, or 3 h prior to a 5-min test. ^bP<0.05, ^cP<0.01 vs vehicle-treated mice. Veh, vehicle.

Figure 7

Effects of a single administration of Neu-P11 and melatonin on the percentage of time spent on the open arms (A), the percentage of the open arms entries (B) and the number of the closed arms entries (C) in the elevated plus-maze model in mice. Neu-P11 (50 mg/kg) and melatonin (50 mg/kg) was injected 2 h prior to a 5 min test in the morning or in the afternoon, respectively. ^bP<0.05, ^cP<0.01 vs vehicle-treated mice at the same test session. ^fP<0.01 vs melatonin-treated mice at the same test session. Veh, vehicle; Mel, melatonin.