Geyer M A, Swerdlow N R, Lehmann-Masten V, Teschendorf H J, Traut M, Gross G
Department of Psychiatry, University of California at San Diego, San Diego, California, USA.
J Pharmacol Exp Ther. 1999 Aug;290(2):716-24.
LU-111995 is a novel antipsychotic drug in clinical development. It has a clozapine-like receptor profile and affinities for dopamine D(4) and 5-hydroxytryptamine(2A) receptors. The effects of LU-111995 were examined in three models of disrupted prepulse inhibition (PPI) in rats. The first model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the dopamine agonist apomorphine. LU-111995 significantly reduced the effect of apomorphine on PPI but also slightly increased PPI by itself. Thus, the increases in PPI were not specific to the animals treated with apomorphine but reflected an effect of LU-111995 on PPI. LU-111995 also attenuated the apomorphine-induced increase in startle reactivity. The second model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the psychotomimetic phencyclidine (PCP). LU-111995 significantly blocked the PCP-induced increase in startle reactivity but did not alter the PPI-disruptive effects of PCP. The third model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by isolation-reared rats tested as adults. Isolation rearing of rats produced deficits in PPI. LU-111995 reversed the isolation rearing-induced deficit in PPI without having any significant effect on PPI in socially reared rats. In summary, LU-111995 exhibits potential antipsychotic-like activity in two models of disrupted PPI. It remains to be elucidated whether its effects on PPI can be attributed to a blockade of single dopamine and 5-hydroxytryptamine receptor subtypes, especially D(4) and 5-hydroxytryptamine(2A), or a combination of both.
LU - 111995是一种正处于临床开发阶段的新型抗精神病药物。它具有类似氯氮平的受体特征，对多巴胺D(4)和5 - 羟色胺(2A)受体有亲和力。在大鼠的三种前脉冲抑制（PPI）破坏模型中研究了LU - 111995的作用。第一个模型检验了这样的假设，即LU - 111995会使接受多巴胺激动剂阿扑吗啡治疗的大鼠所表现出的PPI缺陷恢复正常。LU - 111995显著降低了阿扑吗啡对PPI的影响，但自身也轻微增加了PPI。因此，PPI的增加并非阿扑吗啡治疗动物所特有，而是反映了LU - 111995对PPI的作用。LU - 111995还减弱了阿扑吗啡诱导的惊吓反应性增加。第二个模型检验了这样的假设，即LU - 111995会使接受拟精神病药物苯环利定（PCP）治疗的大鼠所表现出的PPI缺陷恢复正常。LU - 111995显著阻断了PCP诱导的惊吓反应性增加，但未改变PCP对PPI的破坏作用。第三个模型检验了这样的假设，即LU - 111995会使成年后接受测试的隔离饲养大鼠所表现出的PPI缺陷恢复正常。大鼠的隔离饲养导致PPI缺陷。LU - 111995逆转了隔离饲养诱导的PPI缺陷，而对群居饲养大鼠的PPI没有任何显著影响。总之，LU - 111995在两种PPI破坏模型中表现出潜在的抗精神病样活性。其对PPI的作用是否可归因于对单一多巴胺和5 - 羟色胺受体亚型（尤其是D(4)和5 - 羟色胺(2A)）的阻断，还是两者的组合，仍有待阐明。
