Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT(3) receptor antagonist: an investigation in behaviour-based rodent models of depression

Abstract

Aim: The present study was designed to investigate the antidepressant potential of (4-phenylpiperazin-1-yl) (quinoxalin-3-yl) methanone (4a), a novel 5-HT(3) receptor antagonist, with an optimal log P (2.84) and pA(2) value (7.3) greater than ondansetron (6.9) using rodent behavioural models of depression.

Materials and methods: Swiss albino mice were used in actophotometer test, forced swim test (FST) and 5-hydroxytryptophan (5-HTP) induced head twitch response. Reserpine induced hypothermia (RIH) and olfactory bulbectomy were performed in male Wistar rats. Statistical analysis was carried out by using one-way analysis of variance followed by Tukey's test.

Results: Acute treatment of 4a (1-4 mg/kg, i.p.) in mice produced antidepressant-like effects in FST without affecting the baseline locomotion in actophotometer test. Further, 4a (2-4 mg/kg, i.p.) potentiated the 5-HTP induced head twitches response in mice and also antagonized RIH in rats. Furthermore, sub-chronic (14 days) treatment with 4a (2-4 mg/ kg, p.o.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in modified open field exploration.

Conclusions: These preliminary investigations confirm that 4a exhibits antidepressant-like activity in behaviour based rodent models of depression.

Keywords: (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone; 4a; 5-HT3 receptor antagonist; depression; forced swim test; olfactory bulbectomy.

Figure 1

Effect of 4a (0.5-4 mg/kg, i.p.) and fluoxetine (FLX) (10 mg/ kg, i.p.) treatment on the duration of immobility in mouse Forced swim test. Each column represents the mean duration of immobility in sec. (s). The error bars indicate the Standard Error of Mean, ^*P < 0.05 when compared with the vehicle treated group; n = 8 / group

Figure 2

The effect of 4a (2-4 mg/kg, i.p.) and fluoxetine (FLX) (10 mg/kg, i.p.) on the 5-HTP and Pargyline induced head twitch response in mice. Each column represents the mean number of head twitches during a 30 minutes. Control group animals were administered 5-hydroxytryptophan (5 mg/kg, i.p.) and pargyline (75 mg/kg, i.p.). Error bars represent the Standard Error of Mean, ^*P < 0.05 when compared to the control group; n = 6 / group

Figure 3

The effect of 4a (2-4 mg/kg, i.p.) and fluoxetine (FLX) (10 mg/ kg, i.p.) treatment on reserpine induced hypothermia in rats. Each column represents the mean decrease in rectal temperature (°F). Error bars represent the Standard Error of Mean, *P < 0.05 when compared to the 2^nd hour value of vehicle treated group, n = 6 / group

Figure 4

Effect of 4a (2-4 mg /kg, p.o.) and fl uoxetine (10 mg/kg, p.o.) on the ambulation scores of sham/olfactory bulbectomized (OBX) rats in the modifi ed open field test. Each column represents the mean ambulation score. Error bars represent the Standard Error of Mean. ^*P < 0.05 when compared to the sham control, #P < 0.05 when compared to the vehicle treated OBX group. n = 6/ group

Figure 5

Effect of 4a (2-4 mg /kg, p.o.) and fl uoxetine (10 mg/kg, p.o.) on the rearing behaviour of sham/olfactory bulbectomized (OBX) rats in the modifi ed open fi eld test. Each column represents the mean rearing score. Error bars represent the standard error of mean. ^*P < 0.05 when compared to the sham control, #P < 0.05 when compared to the vehicle treated OBX group. n = 6/ group

Figure 6

Effect of 4a (2-4 mg /kg, p.o.) and fl uoxetine (10 mg/kg, p.o.) on the fecal pellets of sham/olfactory bulbectomized (OBX) rats in the modifi ed open fi eld test. Each column represents the mean fecal pellets. Error bars represent the Standard Error of Mean. ^*P < 0.05 when compared to the sham control, #P < 0.05 when compared to the vehicle treated OBX group. n = 6/ group