Inhibition of 5α-reductase in the nucleus accumbens counters sensorimotor gating deficits induced by dopaminergic activation.
Inhibition of 5α-reductase in the nucleus accumbens counters sensorimotor gating deficits induced by dopaminergic activation.
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DOI：
10.1016/j.psyneuen.2011.09.018
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发表时间：
2012-10
影响因子：
3.7
通讯作者：
Bortolato, Marco
中科院分区：
文献类型：
--
作者：
Devoto, Paola;Frau, Roberto;Bini, Valentina;Pillolla, Giuliano;Saba, Pierluigi;Flore, Giovanna;Corona, Marta;Marrosu, Francesco;Bortolato, Marco
关键词：
有力的证据强调了神经类固醇和雄激素在精神分裂症中的关键作用。我们最近报道了抑制类固醇5α-还原酶（5αR），即神经类固醇合成和雄激素代谢的限速酶，在人类和动物模型中引起抗精神病样作用，而不会引起锥体外系副作用。为了阐明介导这些效应的解剖学基础，我们研究了外周和神经结构对5αR抑制剂非那雄胺（FIN）对声惊反射（ASR）脉冲前抑制（PPI）的行为影响的贡献，ASR是一种模拟精神分裂症和其他神经精神疾病中观察到的感觉运动门控损伤的大鼠范式。通过测量该指数的百分比（%PPI）和绝对值（ΔPPI）来排除药物诱导的ASR修饰对PPI的潜在影响。在去兰科和假手术大鼠中，FIN均能阻止多巴胺（DA）受体兴奋剂阿波啡（APO, 0.25 mg/kg， SC）和d-安非他明（AMPH, 2.5 mg/kg， SC）诱导的%PPI缺陷，尽管后者的作用未得到ΔPPI分析的证实。相反，apo诱导的PPI缺陷可通过脑室（10 μg/1 μl）和伏隔核（NAc）壳核（0.5 μg/0.5 μl/侧）注入FIN来抵消。在其他脑区，包括尾状背、杏仁核基底外侧、海马腹侧和内侧前额叶皮质，注射FIN后未观察到明显的ppi改善效果，尽管后者有统计学趋势。全身给药可增加NAc中DA的外排，而脑内给药不增加。综上所述，这些发现表明5αR在门控调节中的作用是基于NAc的突触后机制，而与该区域DA外排的改变没有直接关系。
Cogent evidence highlights a key role of neurosteroids and androgens in schizophrenia. We recently reported that inhibition of steroid 5α-reductase (5αR), the rate-limiting enzyme in neurosteroid synthesis and androgen metabolism, elicits antipsychotic-like effects in humans and animal models, without inducing extrapyramidal side effects. To elucidate the anatomical substrates mediating these effects, we investigated the contribution of peripheral and neural structures to the behavioral effects of the 5αR inhibitor finasteride (FIN) on the prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a rat paradigm that dependably simulates the sensorimotor gating impairments observed in schizophrenia and other neuropsychiatric disorders. The potential effect of drug-induced ASR modifications on PPI was excluded by measuring this index both as percent (%PPI) and absolute values (ΔPPI). In both orchidectomized and sham-operated rats, FIN prevented the %PPI deficits induced by the dopamine (DA) receptor agonists apomorphine (APO, 0.25 mg/kg, SC) and d-amphetamine (AMPH, 2.5 mg/kg, SC), although the latter effect was not corroborated by ΔPPI analysis. Conversely, APO-induced PPI deficits were countered by FIN infusions in the brain ventricles (10 μg/1 μl) and in the nucleus accumbens (NAc) shell and core (0.5 μg/0.5 μl/side). No significant PPI-ameliorating effect was observed following FIN injections in other brain regions, including dorsal caudate, basolateral amygdala, ventral hippocampus and medial prefrontal cortex, although a statistical trend was observed for the latter region. The efflux of DA in NAc was increased by systemic, but not intracerebral FIN administration. Taken together, these findings suggest that the role of 5αR in gating regulation is based on post-synaptic mechanisms in the NAc, and is not directly related to alterations in DA efflux in this region.
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