Differences in sympathetic nervous system activity and NMDA receptor levels within the hypothalamic paraventricular nucleus in rats with differential ejaculatory behavior
Jia-Dong Xia, Jie Chen, Bai-Bing Yang, Hai-Jian Sun, Guo-Qing Zhu, Yu-Tian Dai, Jie Yang, Zeng-Jun Wang, Jia-Dong Xia, Jie Chen, Bai-Bing Yang, Hai-Jian Sun, Guo-Qing Zhu, Yu-Tian Dai, Jie Yang, Zeng-Jun Wang
Abstract
Differences in intravaginal ejaculation latency reflect normal biological variation, but the causes are poorly understood. Here, we investigated whether variation in ejaculation latency in an experimental rat model is related to altered sympathetic nervous system (SNS) activity and expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus of the hypothalamus (PVN). Male rats were classified as "sluggish," "normal," and "rapid" ejaculators on the basis of ejaculation frequency during copulatory behavioral testing. The lumbar splanchnic nerve activity baselines in these groups were not significantly different at 1460 ± 480 mV, 1660 ± 600 mV, and 1680 ± 490 mV, respectively (P = 0.71). However, SNS sensitivity was remarkably different between the groups (P < 0.01), being 28.9% ± 8.1% in "sluggish," 48.4% ± 7.5% in "normal," and 88.7% ± 7.4% in "rapid" groups. Compared with "normal" ejaculators, the percentage of neurons expressing NMDA receptors in the PVN of "rapid" ejaculators was significantly higher, whereas it was significantly lower in "sluggish" ejaculators (P = 0.01). In addition, there was a positive correlation between the expression of NMDA receptors in the PVN and SNS sensitivity (r = 0.876, P = 0.02). This study shows that intravaginal ejaculatory latency is associated with SNS activity and is mediated by NMDA receptors in the PVN.
Keywords: N-methyl-D-aspartic acid receptor; ejaculation; paraventricular nucleus; sympathetic nervous system.
Conflict of interest statement
All authors declared no competing interests
Figures
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References
- Althof SE, McMahon CG, Waldinger MD, Serefoglu EC, Shindel AW, et al. An update of the International Society of Sexual medicine's guidelines for the diagnosis and treatment of premature ejaculation (PE) Sex Med. 2014;2:60–90.
- Buvat J. Pathophysiology of premature ejaculation. J Sex Med. 2011;8(Suppl 4):316–27.
- Larsson K, Ahlenius S. Brain and sexual behavior. Ann N Y Acad Sci. 1999;877:292–308.
- Pfaus JG. Neurobiology of sexual behavior. Curr Opin Neurobiol. 1999;9:751–8.
- Giuliano F. Neurophysiology of erection and ejaculation. J Sex Med. 2011;8(Suppl 4):310–5.
- Pattij T, Olivier B, Waldinger MD. Animal models of ejaculatory behavior. Curr Pharm Des. 2005;11:4069–77.
- Coolen LM, Allard J, Truitt WA, McKenna KE. Central regulation of ejaculation. Physiol Behav. 2004;83:203–15.
- Argiolas A, Melis MR. Neuropeptides and central control of sexual behaviour from the past to the present: a review. Prog Neurobiol. 2013;108:80–107.
- Veening JG, Coolen LM. Neural mechanisms of sexual behavior in the male rat: emphasis on ejaculation-related circuits. Pharmacol Biochem Behav. 2014;121:170–83.
- Xia JD, Chen J, Sun HJ, Zhou LH, Zhu GQ, et al. Centrally mediated ejaculatory response via sympathetic outflow in rats: role of N-methyl-D-aspartic acid receptors in paraventricular nucleus. Andrology. 2017;5:153–9.
- Waldinger MD, Olivier B. Selective serotonin reuptake inhibitor-induced sexual dysfunction: clinical and research considerations. Int Clin Psychopharmacol. 1998;13(Suppl 6):S27–33.
- Waldinger MD, Olivier B. Animal models of premature and retarded ejaculation. World J Urol. 2005;23:115–8.
- Xia JD, Zhou LH, Yang BB, Chen Y, Dai YT. Establishment of an animal model of primary ejaculation. Natl J Androl. 2016;22:579–83.
- National Research Council. Washington (DC): National Academies Press; 2010. Guide for the Care and use of Laboratory Animals.
- Cassaglia PA, Shi Z, Li B, Reis WL, Clute-Reinig NM, et al. Neuropeptide Y acts in the paraventricular nucleus to suppress sympathetic nerve activity and its baroreflex regulation. J Physiol. 2014;592:1655–75.
- Gomes da Silva AQ, Xavier CH, Campagnole-Santos MJ, Caligiorne SM, Baltatu OC, et al. Cardiovascular responses evoked by activation or blockade of GABA(A) receptors in the hypothalamic PVN are attenuated in transgenic rats with low brain angiotensinogen. Brain Res. 2012;1448:101–10.
- Zhu GQ, Xu Y, Zhou LM, Li YH, Fan LM, et al. Enhanced cardiac sympathetic afferent reflex involved in sympathetic overactivity in renovascular hypertensive rats. Exp Physiol. 2009;94:785–94.
- Herman JP, Eyigor O, Ziegler DR, Jennes L. Expression of ionotropic glutamate receptor subunit mRNAs in the hypothalamic paraventricular nucleus of the rat. J Comp Neurol. 2000;422:352–62.
- Kew JN, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacology (Berl) 2005;179:4–29.
- Paxinos G, Watson C. San Diego: Academic Press; 2007. The Rat Brain in Stereotaxic Coordinates.
- Li YF, Cornish KG, Patel KP. Alteration of NMDA NR1 receptors within the paraventricular nucleus of hypothalamus in rats with heart failure. Circ Res. 2003;93:990–7.
- Borgdorff AJ, Rossler AS, Clement P, Bernabe J, Alexandre L, et al. Differences in the spinal command of ejaculation in rapid ejaculating rats. J Sex Med. 2009;6:2197–205.
- Agmo A. Sexual motivation – An inquiry into events determining the occurrence of sexual behavior. Behav Brain Res. 1999;105:129–50.
- Allouh MZ. Effects of swimming activity on the copulatory behavior of sexually active male rats. Int J Impot Res. 2015;27:113–7.
- Rowland DL, Keeney C, Slob AK. Sexual response in men with inhibited or retarded ejaculation. Int J Impot Res. 2004;16:270–4.
- Barrett CJ. Renal sympathetic nerves – what have they got to do with cardiovascular disease? Exp Physiol. 2015;100:359–65.
- Katholi RE, Whitlow PL, Winternitz SR, Oparil S. Importance of the renal nerves in established two-kidney, one clip goldblatt hypertension. Hypertension. 1982;4(3 Pt 2):166–74.
- Xia JD, Han YF, Zhou LH, Xu ZP, Chen Y, et al. Sympathetic skin response in patients with primary premature ejaculation. Int J Impot Res. 2014;26:31–4.
- Zorba OU, Cicek Y, Uzun H, Cetinkaya M, Onem K, et al. Autonomic nervous system dysfunction in lifelong premature ejaculation: analysis of heart rate variability. Urology. 2012;80:1283–6.
- Pitchers KK, Schmid S, Di Sebastiano AR, Wang X, Laviolette SR, et al. Natural reward experience alters AMPA and NMDA receptor distribution and function in the nucleus accumbens. PLoS One. 2012;7:e34700.
- Fleming AS, Kucera C. Sexual experience effects are blocked both by the protein-synthesis inhibitor, cycloheximide, and by the noncompetitive NMDA antagonist, MK-801. Behav Neural Biol. 1991;56:319–28.
- Bredy TW, Zhang TY, Grant RJ, Diorio J, Meaney MJ. Peripubertal environmental enrichment reverses the effects of maternal care on hippocampal development and glutamate receptor subunit expression. Eur J Neurosci. 2004;20:1355–62.
- Liu D, Diorio J, Day JC, Francis DD, Meaney MJ. Maternal care, hippocampal synaptogenesis and cognitive development in rats. Nat Neurosci. 2000;3:799–806.
- Pyner S. Neurochemistry of the paraventricular nucleus of the hypothalamus: implications for cardiovascular regulation. J Chem Neuroanat. 2009;38:197–208.
Source: PubMed