Evaluation of the Anxiolytic Effect of Ramelteon in Various Rat Models of Anxiety

Abstract

Background Melatonin was found to have anxiolytic properties in several animal and human studies. The melatonin receptor agonist ramelteon might also have a similar anxiolytic action. Objectives The objective of the study was to evaluate the effect of ramelteon in various rat models of anxiety and to explore the possible mechanism of action. Methods The anxiolytic effect was compared between the control group, diazepam group (1 mg/kg and 0.5 mg/kg), and ramelteon group (0.25 mg/kg, 0.5 mg/kg, and 1 mg/kg) by an elevated plus maze, light-dark box, hole board apparatus, and open field test in Sprague Dawley rats. Antagonists flumazenil, picrotoxin, and Luzindole were used to explore the possible mechanism of action of ramelteon if it showed an anxiolytic property. Results Ramelteon as a standalone drug did not show an anxiolytic effect. However, a combination of ramelteon (1 mg/kg) and diazepam (0.5 mg/kg) showed an anxiolytic effect. Conclusion Further studies can evaluate the use of a fixed-dose combination of ramelteon and already-approved anxiolytic drugs to reduce the dose of the latter.

Keywords: animal models; anxiety; melatonin; neuropharmacology; ramelteon.

Figure 1. Rat exploring the open arm of the elevated plus maze

Figure 2. Bar diagram showing the mean time spent in the open arm across different groups in the acute study

R: ramelteon group, D: diazepam group, R+D: ramelteon plus diazepam group

Figure 3. Bar diagram showing the mean time spent in the open arm across different groups in the chronic study

R: ramelteon group, D: diazepam group, R+D: ramelteon plus diazepam group

Figure 4. Head dipping behavior of rats in the hole board apparatus

Figure 5. Bar graph showing the mean number of head dipping across different groups in the acute study

Figure 6. Bar diagram showing the mean number of head dippings across different groups in the chronic study

Figure 7. Bar diagram showing the mean time spent in the light chamber in the LDB test across different groups in the acute study

LDB: light-dark box

Figure 8. Bar diagram showing the mean time spent in the light chamber of the LDB test across different groups in the chronic study

LDB: light-dark box

Figure 9. Bar diagram showing the mean time spent in central squares in the open field test across different groups in the acute study

Figure 10. Bar diagram showing the mean time spent in central squares of the open field test across different groups in the chronic study