Vardenafil Enhances Oxytocin Expression in the Paraventricular Nucleus without Sexual Stimulation
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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.
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.
참고문헌 (35)
- Pedersen CA, "Oxytocin control of maternal behavior. Regulation by sex steroids and offspring stimuli", Ann N Y Acad Sci, 807, pp.126~145 (1997)
- Carter CS, "Neuroendocrine perspectives on social attachment and love", Psychoneuroendocrinology, 23, pp.779~818 (1998)
- Uvnäs-Moberg K, "Oxytocin may mediate the benefits of positive social interaction and emotions", Psychoneuroendocrinology, 23, pp.819~835 (1998)
- Landgraf R, "Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication", Front Neuroendocrinol, 25, pp.150~176 (2004)
- Huber D, "Vasopressin and oxytocin excite distinct neuronal populations in the central amygdala", Science, 308, pp.245~248 (2005)
- Carter CS, "Physiological substrates of mammalian monogamy: the prairie vole model", Neurosci Biobehav Rev, 19, pp.303~314 (1995)
- Witt DM, "Enhanced social interactions in rats following chronic, centrally infused oxytocin", Pharmacol Biochem Behav, 43, pp.855~861 (1992)
- Insel TR, "Oxytocin--a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies", Psychoneuroendocrinology, 17, pp.3~35 (1992)
- Dragunow M, "The use of c-fos as a metabolic marker in neuronal pathway tracing", J Neurosci Methods, 29, pp.261~265 (1989)
- Morgan JI, "Stimulus-transcription coupling in neurons:role of cellular immediate-early genes", Trends Neurosci, 12, pp.459~462 (1989)
- Cullinan WE, "Pattern and time course of immediate early gene expression in rat brain following acute stress", Neuroscience, 64, pp.477~505 (1995)
- De Oliveira RM, "Effects of excitatory amino acids and nitric oxide on flight behavior elicited from the dorsolateral periaqueductal gray", Neurosci Biobehav Rev, 25, pp.679~685 (2001)
- Reffelmann T, "Vardenafil: a selective inhibitor of phosphodiesterase-5 for the treatment of erectile dysfunction", Expert Opin Pharmacother, 8, pp.965~974 (2007)
- Uvnäs-Moberg K, "Influence on plasma levels of somatostatin, gastrin, glucagon, insulin and VIP-like immunoreactivity in peripheral venous blood of anaesthetized cats induced by low intensity afferent stimulation of the sciatic nerve", Acta Physiol Scand, 126, pp.225~230 (1986)
- Volke V, "Augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice", J Physiol Pharmacol, 54, pp.653~660 (2003)
- van Driel MF, "Phosphodiesterase inhibitors: effectiveness and new applications", Ned Tijdschr Geneeskd, 150, pp.1613~1616 (2006)
- Argiolas A, "Neuropeptides and sexual behaviour", Neurosci Biobehav Rev, 23, pp.1127~1142 (1999)
- Ferrini MG, "Vardenafil prevents fibrosis and loss of corporal smooth muscle that occurs after bilateral cavernosal nerve resection in the rat", Urology, 68, pp.429~435 (2006)
- Lee MH, "Naloxone potentiates treadmill running-induced increase in c-Fos expression in rat hippocampus", Life Sci, 73, pp.3139~3147 (2003)
- Hellstrom WJ, "Vardenafil: a new approach to the treatment of erectile dysfunction", Curr Urol Rep, 4, pp.479~487 (2003)
- Wise TN, "Psychosocial side effects of sildenafil therapy for erectile dysfunction", J Sex Marital Ther, 25, pp.145~150 (1999)
- Kovanecz I, "Chronic daily tadalafil prevents the corporal fibrosis and veno-occlusive dysfunction that occurs after cavernosal nerve resection", BJU Int, 101, pp.203~210 (2008)
- Royl G, "Effects of the PDE5-inhibitor vardenafil in a mouse stroke model", Brain Res, 1265, pp.148~157 (2009)
- Gul S, "Effect of vardenafil on cerebral vasospasm following experimental subarachnoid hemorrhage in rats", J Clin Neurosci, 17, pp.1038~1041 (2010)
- Young LJ, "Oxytocin and vasopressin receptors and species-typical social behaviors", Horm Behav, 36, pp.212~221 (1999)
- Gimpl G, "The oxytocin receptor system: structure,function, and regulation", Physiol Rev, 81, pp.629~683 (2001)
- Neumann ID, "Involvement of the brain oxytocin system in stress coping: interactions with the hypothalamo-pituitary-adrenal axis", Prog Brain Res, 139, pp.147~162 (2002)
- Lee PR, "Social interaction deficits caused by chronic phencyclidine administration are reversed by oxytocin", Neuropsychopharmacology, 30, pp.1883~1894 (2005)
- Fries AB, "Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior", Proc Natl Acad Sci U S A, 102, pp.17237~17240 (2005)
- Kosfeld M, "Oxytocin increases trust in humans", Nature, 435, pp.673~676 (2005)
- Zak PJ, "Oxytocin is associated with human trustworthiness", Horm Behav, 48, pp.522~527 (2005)
- Heinrichs M, "Effects of suckling on hypothalamic-pituitary-adrenal axis responses to psychosocial stress in postpartum lactating women", J Clin Endocrinol Metab, 86, pp.4798~4804 (2001)
- Heinrichs M, "Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress", Biol Psychiatry, 54, pp.1389~1398 (2003)
- Kendrick KM, "Intracerebroventricular oxytocin stimulates maternal behaviour in the sheep", Neuroendocrinology, 46, pp.56~61 (1987)
- Witt DM, "Central and peripheral effects of oxytocin administration in prairie voles (Microtus ochrogaster)", Pharmacol Biochem Behav, 37, pp.63~69 (1990)