Gogos Andrea, van den Buuse Maarten
Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC 3052, Australia.
Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC 3052, Australia; School of Psychological Science, La Trobe University, Bundoora, VIC 3086, Australia.
Schizophr Res. 2015 Nov;168(3):634-9. doi: 10.1016/j.schres.2015.04.029. Epub 2015 Jun 5.
Evidence suggests that oestrogen plays a protective role against the development and severity of schizophrenia. However, while oestrogen may be beneficial as a treatment in schizophrenia, its chronic use is associated with side-effects. Selective oestrogen receptor modulators (SERMs) may provide an alternative, however little is known about the mechanism underlying their effects in schizophrenia.
We investigated the effect of raloxifene and tamoxifen on dopaminergic-induced disruptions of prepulse inhibition (PPI). PPI measures sensorimotor gating and PPI disruptions are considered an endophenotype for schizophrenia. Adult female Sprague-Dawley rats were either intact, ovariectomized (OVX), OVX and 17β-oestradiol-treated, OVX and raloxifene-treated (low or high dose), or OVX and tamoxifen-treated (low or high dose).
The dopamine D1/D2 receptor agonist, apomorphine (0, 0.1, 0.3 and 1mg/kg), caused the expected dose-dependent disruption in PPI in intact and OVX rats. This PPI disruption was prevented in OVX rats treated with 17β-oestradiol, a high dose of raloxifene or a high dose of tamoxifen. In untreated OVX rats, average PPI was 55% after saline and 34% after 1mg/kg apomorphine treatment, a reduction of 21%. However, oestradiol-treated and raloxifene-treated OVX rats showed only a 7% PPI reduction, and tamoxifen-treated OVX rats had a 4% PPI reduction caused by apomorphine treatment. Startle amplitude was not different between the groups.
The SERMs, raloxifene and tamoxifen, can prevent dopamine D1/D2 receptor-mediated disruptions of sensorimotor gating, similar to oestradiol. These data lend support for the use of SERMs as a treatment for schizophrenia.
有证据表明，雌激素对精神分裂症的发生和严重程度具有保护作用。然而，虽然雌激素作为精神分裂症的一种治疗方法可能有益，但其长期使用会产生副作用。选择性雌激素受体调节剂（SERM）可能提供一种替代方案，然而对于它们在精神分裂症中发挥作用的潜在机制知之甚少。
我们研究了雷洛昔芬和他莫昔芬对多巴胺能诱导的前脉冲抑制（PPI）破坏的影响。PPI测量感觉运动门控，PPI破坏被认为是精神分裂症的一种内表型。成年雌性斯普拉格-道利大鼠分为完整组、卵巢切除组（OVX）、卵巢切除并接受17β-雌二醇治疗组、卵巢切除并接受雷洛昔芬治疗组（低剂量或高剂量）或卵巢切除并接受他莫昔芬治疗组（低剂量或高剂量）。
多巴胺D1/D2受体激动剂阿扑吗啡（0、0.1、0.3和1mg/kg）在完整和OVX大鼠中引起了预期的剂量依赖性PPI破坏。在接受17β-雌二醇、高剂量雷洛昔芬或高剂量他莫昔芬治疗的OVX大鼠中，这种PPI破坏得到了预防。在未治疗的OVX大鼠中，生理盐水注射后平均PPI为55%，1mg/kg阿扑吗啡治疗后为34%，降低了21%。然而，接受雌二醇治疗和雷洛昔芬治疗的OVX大鼠中，阿扑吗啡治疗引起的PPI降低仅为7%，接受他莫昔芬治疗的OVX大鼠中PPI降低为4%。各组之间的惊吓幅度没有差异。
SERM雷洛昔芬和他莫昔芬可以预防多巴胺D1/D2受体介导的感觉运动门控破坏，类似于雌二醇。这些数据支持将SERM用作精神分裂症的一种治疗方法。
