Mental Health Research Institute, Parkville, VIC, Australia.
Department of Pharmacology, University of Melbourne, Melbourne, VIC, Australia.
Psychopharmacology (Berl). 2017 Sep;234(18):2727-2735. doi: 10.1007/s00213-017-4668-8. Epub 2017 Jul 3.
Altered glutamate NMDA receptor function is implicated in schizophrenia, and gender differences have been demonstrated in this illness.
This study aimed to investigate the interaction of gonadal hormones with NMDA receptor-mediated locomotor hyperactivity and PPI disruption in mice.
The effect of 0.25 mg/kg of MK-801 on locomotor activity was greater in male mice than in female mice. Gonadectomy (by surgical castration) significantly reduced MK-801-induced hyperlocomotion in male mice, but no effect of gonadectomy was seen in female mice or on amphetamine-induced locomotor hyperactivity. The effect of MK-801 on prepulse inhibition of startle (PPI) was similar in intact and castrated male mice and in ovariectomized (OVX) female mice. In contrast, there was no effect of MK-801 on PPI in intact female mice. Forebrain NMDA receptor density, as measured with [H]MK-801 autoradiography, was significantly higher in male than in female mice but was not significantly altered by either castration or OVX.
These results suggest that male sex hormones enhance the effect of NMDA receptor blockade on psychosis-like behaviour. This interaction was not seen in female mice and was independent of NMDA receptor density in the forebrain. Male sex hormones may be involved in psychosis by an interaction with NMDA receptor hypofunction.
谷氨酸 NMDA 受体功能的改变与精神分裂症有关，并且在这种疾病中已经表现出性别差异。
本研究旨在研究性腺激素与 NMDA 受体介导的运动过度兴奋和 PPI 破坏在小鼠中的相互作用。
0.25mg/kgMK-801 对雄性小鼠的运动活性的影响大于雌性小鼠。去势（通过手术去势）显著降低了雄性小鼠中 MK-801 诱导的过度运动，但在雌性小鼠或安非他命诱导的运动过度兴奋中未见去势的影响。MK-801 对惊跳前抑制（PPI）的影响在完整和去势的雄性小鼠以及卵巢切除（OVX）的雌性小鼠中相似。相比之下，MK-801 对完整雌性小鼠的 PPI 没有影响。用 [H]MK-801 放射自显影术测量的前额叶 NMDA 受体密度在雄性小鼠中明显高于雌性小鼠，但无论是去势还是 OVX 都没有明显改变。
这些结果表明，雄性性激素增强了 NMDA 受体阻断对类精神病行为的影响。这种相互作用在雌性小鼠中没有出现，并且与前额叶 NMDA 受体密度无关。雄性性激素可能通过与 NMDA 受体功能低下的相互作用参与精神病。
