Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists
Modulation of prepulse inhibition and stereotypies in rodents: no evidence for antipsychotic-like properties of histamine H3-receptor inverse agonists
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DOI：
10.1007/s00213-010-1863-2
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发表时间：
2010-07-01
影响因子：
3.4
通讯作者：
Arrang, Jean-Michel
中科院分区：
文献类型：
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作者：
Burban, Aude;Sadakhom, Chit;Arrang, Jean-Michel
h -3受体逆激动剂作为一些中枢疾病的创新疗法引起了极大的兴趣。尽管它们的前认知特性已被证实，但它们的抗精神病药物样特性仍存在争议。我们进一步探讨了三种选择性h -3受体拮抗剂环丙昔芬、BF2.649和ABT-239的最大剂量（3-10 mg/kg）对阿波啡、MK-801和苯环利定（PCP）诱导的脉前抑制（PPI）缺陷的影响。研究了它们对阿波啡和甲基苯丙胺诱导的刻板印象的影响。环丙昔芬、BF2.649和ABT-239不能逆转阿波啡（0.5 mg/kg，皮下）对大鼠PPI的损害。环丙昔芬和BF2.649不能逆转MK-801 （0.3 mg/kg）对小鼠造成的损伤。Ciproxifan和BF2.649也不能逆转PCP （5-10 mg/kg）对小鼠造成的破坏。低至中等剂量氟哌啶醇（0.1-0.4 mg/kg，腹腔注射），单独或与BF2.649联合给药，不能逆转mk -801诱导的PPI中断。高剂量（1 mg/kg）氟哌啶醇部分逆转mk -801诱导的缺陷，BF2.649倾向于增加这种作用，尽管不显著。氟哌啶醇完全抑制阿波啡和甲基苯丙胺诱导的小鼠刻板印象，而环丙昔芬对阿波啡的抑制作用是部分的，对甲基苯丙胺的抑制作用非常低。在几个已验证的疾病动物模型中，它们完全没有作用，这并不支持h -3受体逆激动剂的抗精神病特性。然而，先前报道的h -3受体逆激动剂在处理学习、注意力和记忆的行为任务中的积极作用，维持了h -3受体逆激动剂作为辅助药物治疗精神分裂症认知症状的兴趣。
H-3-receptor inverse agonists raise a great interest as innovative therapeutics in several central disorders. Whereas their procognitive properties are well established, their antipsychotic-like properties are still debated.We further explored the effect of maximal doses (3-10 mg/kg) of ciproxifan, BF2.649, and ABT-239, three selective H-3-receptor inverse agonists, on deficits of prepulse inhibition (PPI) induced by apomorphine, MK-801, and phencyclidine (PCP). Their effect was also investigated on stereotypies induced by apomorphine and methamphetamine.Ciproxifan, BF2.649, and ABT-239 did not reverse the PPI impairment produced by apomorphine (0.5 mg/kg, subcutaneous) in rats. Ciproxifan and BF2.649 did not reverse the impairment induced in mice by MK-801 (0.3 mg/kg). Ciproxifan and BF2.649 also failed to reverse the disruption induced in mice by PCP (5-10 mg/kg). Low to moderate doses of haloperidol (0.1-0.4 mg/kg, intraperitoneal), alone or co-administered with BF2.649, did not reverse MK-801-induced PPI disruption. A high dose (1 mg/kg) of haloperidol partially reversed the MK-801-induced deficit and BF2.649 tended to increase this effect, although nonsignificantly. Whereas stereotypies induced in mice by apomorphine and methamphetamine were totally suppressed by haloperidol, the decrease induced by ciproxifan was partial against apomorphine and very low, if any, against methamphetamine.Their total absence of effect in several validated animal models of the disease does not support antipsychotic properties of H-3-receptor inverse agonists. However, their positive effects previously reported in behavioral tasks addressing learning, attention, and memory maintain the interest of H-3-receptor inverse agonists for the treatment of cognitive symptoms of schizophrenia as adjunctive medications.