Blockage of N-methyl-D-aspartate receptors decreases testosterone levels and enhances postnatal neuronal apoptosis in the preoptic area of male rats

Sexual dimorphism has been found in the preoptic area of the hypothalamus ( POA), a major site of glutamate actions via N-methyl-D-aspartate (NMDA) rec eptors. The sexually dimorphic nucleus of the preoptic area (SDN-POA) of ma le rats exhibits about seven-fold greater nuclear volume than that of femal es. A naturally occurring neonatal neuronal apoptosis, that can be prevente d by testosterone, may contribute to this sexual difference in SDN-POA nucl ear volume. Since activation of NMDA receptors in the POA induces GnRH secr etion, it may be involved in both elevation of serum testosterone and preve ntion of neuronal death in the SDN-POA. In the present study, protein expre ssion of NMDA receptors in the POA of male and female fetuses was quantifie d on the day preceding the fetal testosterone peak (embryonic day 16; ED 16 ). Rats were then distributed in four groups: (1) untreated males, (2) untr eated females, (3) males pretreated with MK-801 (a noncompetitive NMDA rece ptor antagonist), and (4) females pretreated with MK-801. Serum levels of t estosterone were estimated on the afternoon of ED 18. Expression of Bcl-2 a nd Bar, as well as neuronal apoptosis in SDN-POA, were observed on postnata l day 8. The results showed that (I)expression of NMDA receptors in the POA of male fetuses was higher than that of females on ED 16; (2) levels of te stosterone were lower in MK-801 pretreated male fetuses than in intact male s on ED 18; (3) expression of Bcl-2 in the POA of MK-801 pretreated male ra ts was significantly less than that of control males; (4) the apoptotic inc idence in the SDN-POA of MK-801 pretreated male rats was significantly grea ter than in control males, while there was no significant difference in apo ptotic incidence in the SDN-POA between MK-801 pretreated and intact female s. These results suggest that the NMDA receptor is highly expressed in pren atal male fetuses, and that it might play an important role in the elevatio n of testosterone levels. Moreover, activation of NMDA receptors may protec t SDN-POA neurons from naturally occurring neuronal death, by modulating te stosterone and/or Bcl-2 expression. Copyright (C) 2000 S. Karger AG. Basel.