Vardenafil Enhances Oxytocin Expression in the Paraventricular Nucleus without Sexual Stimulation

Abstract

Purpose: Oxytocin is associated with the ability to form normal social attachments. c-Fos is an immediate early gene whose expression is used as a marker for stimulus-induced changes in neurons. The effect of phosphodiesterase-5 (PDE-5) inhibitors on oxytocin activation in the brain without sexual stimuli has not yet been reported. In the present study, we investigated the effects of vardenafil on oxytocin and c-Fos expression in the paraventricular nucleus (PVN) of conscious rats.

Methods: Male Sprague-Dawley rats weighing 300±10 g were divided into 6 groups (n=5 in each group): the control group, the 1-day-0.5 mg/kg, the 1-day-1 mg/kg, the 1-day-2 mg/kg, the 3-day-1 mg/kg, and the 7-day-1 mg/kg vardenafil administration group. The experiment was conducted without sexual stimulation. Vardenafil was orally administered. The animals in the control group received an equivalent amount of distilled water orally. The expression of oxytocin and c-Fos in the PVN was detected by immunohistochemistry.

Results: Oxytocin expression in the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil appeared in a duration-dependent manner. c-Fos in the oxytocin neurons of the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil also appeared in a duration-dependent manner. These results showed that vardenafil augments the expression of oxytocin with activation of oxytocin neurons in the PVN.

Conclusions: In this study, we showed that the PDE-5 inhibitor, vardenafil directly enhances oxytocin expression and also activates oxytocin neurons in the PVN, which indicates that vardenafil may exert positive effects on affiliation behavior and social interaction.

Keywords: Oxytocin; Paraventricular nucleus; Rats; Vardenafil; c-Fos.

Fig. 1

The dose dependence of the effect of 1-day vardenafil administration on oxytocin expression in the paraventricular nucleus. Above: Photomicrographs of oxytocin-positive neurons. (1) Control group, (2) 2 mg/kg vardenafil administration group. The scale bar represents 100 µm. Below: Mean number of oxytocin neurons in each group. (A) Control group, (B) 0.5 mg/kg vardenafil administration group, (C) 1 mg/kg vardenafil administration group, (D) 2 mg/kg vardenafil administration group. Values are mean±standard error of the mean. ^a)Represents P<0.05 compared to the control group. ^b)Represents P<0.05 compared to the 0.5 mg/kg vardenafil administration group. ^c)Represents P<0.05 compared to the 1 mg/kg vardenafil administration group.

Fig. 2

The duration dependence of the effect of 1 mg/kg vardenafil administration on oxytocin expression in the paraventricular nucleus. Above: Photomicrographs of oxytocin-positive neurons. (1) Control group, (2) 7-day vardenafil administration group. The scale bar represents 100 µm. Below: Mean number of oxytocin neurons in each group. (A) Control group, (B) 1-day vardenafil administration group, (C) 3-day vardenafil administration group, (D) 7-day vardenafil administration group. Values are mean±standard error of the mean. ^a)Represents P<0.05 compared to the control group. ^b)Represents P<0.05 compared to the 1-day vardenafil administration group. ^c)Represents P<0.05 compared to the 3-day vardenafil administration group.

Fig. 3

The dose dependence of the effect of 1-day vardenafil administration on the percentage of c-Fos-positive oxytocin neurons in the paraventricular nucleus. Above: Photomicrographs of c-Fos-positive oxytocin neurons in the paraventricular nucleus. (1) Control group, (2) 2 mg/kg vardenafil administration group. The scale bar represents 100 µm. Below: Mean percentage of c-Fos-positive oxytocin neurons in each group. (A) Control group, (B) 0.5 mg/kg vardenafil administration group, (C) 1 mg/kg vardenafil administration group, (D) 2 mg/kg vardenafil administration group. Values are mean±standard error of the mean. ^a)Represents P<0.05 compared to the control group. ^b)Represents P<0.05 compared to the 0.5 mg/kg vardenafil administration group. ^c)Represents P<0.05 compared to the 1 mg/kg vardenafil administration group.

Fig. 4

The duration dependence of the effect of 1 mg/kg vardenafil administration on the percentage of c-Fos-positive oxytocin neurons in the paraventricular nucleus. Above: Photomicrographs of c-Fos-positive oxytocin neurons. (1) Control group, (2) 7-day vardenafil administration group. The scale bar represents 100 µm. Below: Mean percentage of c-Fos-positive oxytocin neurons in each group. (A) Control group, (B) 1-day vardenafil administration group, (C) 3-day vardenafil administration group, (D) 7-day vardenafil administration group. Values are mean±standard error of the mean. ^a)Represents P<0.05 compared to the control group. ^b)Represents P<0.05 compared to the 1-day vardenafil administration group. ^c)Represents P<0.05 compared to the 3-day vardenafil administration group.