Antipsychotic-Like Properties of 5-α-Reductase Inhibitors
Antipsychotic-Like Properties of 5-α-Reductase Inhibitors
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DOI：
10.1038/npp.2008.39
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发表时间：
2008-12-01
影响因子：
7.6
通讯作者：
Gessa, Gian L.
中科院分区：
文献类型：
--
作者：
Bortolato, Marco;Frau, Roberto;Gessa, Gian L.
最近的证据表明，神经活性类固醇可能参与精神分裂症谱系障碍的发病机制，但这种参与的机制是难以捉摸的。由于5-α-还原酶（5AR）是脑类固醇生成的两个主要代谢途径之一的限速酶，我们研究了其阻断在几种精神病样行为大鼠模型中的作用。5AR抑制剂非那肽（FIN，60或100 mg/kg，腹膜内，i. p.）剂量和时间依赖性地拮抗阿扑吗啡（APO，0.25 mg/kg，皮下，s.c.）和d-苯丙胺（AMPH，5 mg/kg，s.c.），以类似于氟哌啶醇（HAL，0.1mg/kg，i. p.）和氯氮平（CLO，5 mg/kg，i. p.）。用其他5AR抑制剂度他雄胺（DUT，40或80 mg/kg，i. p.）和SKF 105111（30 mg/kg，i.p.）。FIN（60或100 mg/kg，i.p.）也减少由AMPH（1或3 mg/kg，s.c.）对APO（0.25 mg/kg，s.c.）诱导的刻板行为有明显的抑制作用。然而，FIN（100 mg/kg，i. p.）不能逆转N-甲基-d-天冬氨酸受体拮抗剂地佐环平（0.1 mg/kg，s.c.）诱导的PPI破坏。FIN（60-300 mg/kg，i.p.）在棒试验或爪试验中均未诱导僵硬症。我们的研究结果表明，5AR抑制剂在动物中引起抗精神病样作用，并可能被提出作为一个假定的新的目标，在精神疾病的管理。
Recent evidence indicates that neuroactive steroids may participate in the pathogenesis of schizophrenia spectrum disorders, yet the mechanisms of this involvement are elusive. As 5-alpha-reductase (5AR) is the rate-limiting enzyme of one of the two major metabolic pathways in brain steroidogenesis, we investigated the effects of its blockade in several rat models of psychotic-like behavior. The 5AR inhibitor finasteride ( FIN, 60 or 100 mg/kg, intraperitoneal, i.p.) dose- and time-dependently antagonized prepulse inhibition (PPI) deficits induced by apomorphine ( APO, 0.25 mg/kg, subcutaneous, s.c.) and d-amphetamine ( AMPH, 5 mg/kg, s.c.), in a manner analogous to haloperidol ( HAL, 0.1 mg/kg, i.p.) and clozapine ( CLO, 5 mg/kg, i.p.). Similar results were observed with the other 5AR inhibitors dutasteride ( DUT, 40 or 80 mg/kg, i.p.) and SKF 105111 ( 30 mg/kg, i.p.). FIN ( 60 or 100 mg/kg, i.p.) also reduced hyperlocomotion induced by AMPH ( 1 or 3 mg/kg, s.c.) and attenuated stereotyped behaviors induced by APO ( 0.25 mg/kg, s.c.). Nevertheless, FIN ( 100 mg/kg, i.p.) did not reverse the PPI disruption induced by the N-methyl-d-aspartate receptor antagonist dizocilpine ( 0.1 mg/kg, s.c.). FIN (60-300 mg/kg, i.p.) induced no catalepsy in either the bar test or the paw test. Our results suggest that 5AR inhibitors elicit antipsychotic-like effects in animals and may be proposed as a putative novel target in the management of psychotic disorders.