Dextromethorphan-induced psychotoxic behaviors cause sexual dysfunction in male mice via stimulation of σ-1 receptors.
Dextromethorphan (DM) is a well-known antitussive dextrorotatory morphinan. We and others have demonstrated that sigma (σ) receptors may be important for DM-mediated neuromodulation. Because an earlier report suggested that DM might affect sexual function and that σ receptor ligands affect signaling pathways in the periphery, we examined whether DM-induced psychotoxic burden affected male reproductive function. We observed that DM had a high affinity at σ-1 receptors in the brain and testis but relatively low affinity at σ-2 receptors. Prolonged treatment with DM resulted in conditioned place preference and hyperlocomotion, followed by an increase in Fos-related antigen expression in the nucleus accumbens in male mice. Simultaneously, DM induced significant reductions in gonadotropin-releasing-hormone immunoreactivity in the hypothalamus. Moreover, we observed that DM induced increased sperm abnormalities and decreased sperm viability and sexual behavior. These phenomena were significantly attenuated by combined treatment with BD1047, a σ-1 receptor antagonist, but not by SM-21, a σ-2 receptor antagonist. Thus, these results suggest that DM psychotoxicity might lead to reproductive stress in male mice by activating σ-1 receptors.
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea.
Yunsung
Y
Nam
Eun-Joo
EJ
Shin
Boo-Keun
BK
Yang
Jae-Hyung
JH
Bach
Ji Hoon
JH
Jeong
Yoon Hee
YH
Chung
Eon Sub
ES
Park
Zhengyi
Z
Li
Kee-Won
KW
Kim
Young-Bae
YB
Kwon
Toshitaka
T
Nabeshima
Hyoung-Chun
HC
Kim
D000818:Animals; D003915:Dextromethorphan / Q000009:adverse effects*; D007150:Immunohistochemistry; D008124:Locomotion; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011869:Radioligand Assay; D017480:Receptors, sigma / Q000819:agonists*; D012726:Sexual Behavior, Animal / Q000187:drug effects*; D013081:Sperm Motility / Q000187:drug effects; D000097605:Sigma-1 Receptor
D003915:Dextromethorphan; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor