Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City UT United States; Dept. of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence KS United States.
Dept. of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City UT United States.
Psychoneuroendocrinology. 2019 Oct;108:53-61. doi: 10.1016/j.psyneuen.2019.06.009. Epub 2019 Jun 14.
The extraction of salient information from the environment is modulated by the activation of dopamine receptors. Using rodent models, we previously reported that gating deficits caused by dopamine receptor activation - as measured by the prepulse inhibition (PPI) of startle - are effectively opposed by inhibitors of the steroidogenic enzyme 5α-reductase (5αR). The specific 5αR isoenzyme and steroids implicated in these effects, however, remain unknown.
The effects of the selective D dopamine receptor agonist SKF-82958 (SKF, 0.3 mg/kg, IP) and D receptor agonist quinpirole (QUIN, 0.5 mg/kg, IP) were tested in the startle reflex and PPI of knockout (KO) mice for either 5αR type 1 (5αR1) or type 2 (5αR2). Furthermore, we established whether these effects may be modified by the 5α-reduced steroids dihydroprogesterone (DHP), allopregnanolone (AP), dihydrotestosterone (DHT), 5α-androstane-3α,17β-diol (3α-diol), or androsterone. To test the mechanisms whereby 5αR products may alter the PPI-disrupting properties of D agonists, we studied the involvement of GABA-A and PXR, two receptors targeted by neuroactive steroids. Specifically, we tested the effects of SKF in combination with the GABA-A antagonist bicuculline, as well as in KO mice for the GABA-A δ subunit and PXR.
5αR1, but not 5αR2, knockout (KO) mice were insensitive to the PPI-disrupting effects of SKF. This sensitivity was reinstated by AP (3 mg/kg, IP), but not other 5α-reduced steroids. The PPI deficits induced by SKF were not modified by bicuculline, δ-subunit KO mice and PXR KO mice.
These results collectively suggest that 5αR1 enables the negative effects of D dopamine receptor activation on information processing via production of AP. The contribution of AP to the PPI-disrupting mechanisms of D receptor agonists, however, do not appear to be mediated by either GABA-A or PXR receptors.
多巴胺受体的激活调节了从环境中提取显著信息的能力。我们之前使用啮齿动物模型报告，多巴胺受体激活引起的门控缺陷——如惊跳反射的前脉冲抑制（PPI）所测量的——可被甾体生成酶 5α-还原酶（5αR）的抑制剂有效拮抗。然而，这些作用涉及的确切 5αR 同工酶和类固醇仍不清楚。
我们在 5αR 类型 1（5αR1）或 2（5αR2）敲除（KO）小鼠中测试了选择性 D 多巴胺受体激动剂 SKF-82958（SKF，0.3mg/kg，IP）和 D 受体激动剂喹吡罗（QUIN，0.5mg/kg，IP）对惊跳反射和 PPI 的影响。此外，我们确定这些影响是否可以通过 5α 还原的类固醇二氢孕酮（DHP）、别孕烯醇酮（AP）、二氢睾酮（DHT）、5α-雄烷-3α,17β-二醇（3α-二醇）或雄酮来改变。为了测试 5αR 产物可能改变 D 激动剂破坏 PPI 属性的机制，我们研究了神经活性类固醇靶向的 GABA-A 和 PXR 两种受体的参与情况。具体而言，我们测试了 SKF 与 GABA-A 拮抗剂荷包牡丹碱联合使用的效果，以及 GABA-A δ 亚基和 PXR 的 KO 小鼠中的效果。
5αR1，但不是 5αR2，KO 小鼠对 SKF 破坏 PPI 的作用不敏感。AP（3mg/kg，IP）可恢复这种敏感性，但其他 5α 还原类固醇则不行。SKF 引起的 PPI 缺陷不受荷包牡丹碱、δ 亚基 KO 小鼠和 PXR KO 小鼠的影响。
这些结果表明，5αR1 使 D 多巴胺受体激活对信息处理的负面影响能够通过产生 AP 来实现。然而，AP 对 D 受体激动剂破坏 PPI 机制的贡献似乎不是由 GABA-A 或 PXR 受体介导的。
