Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like in activity
Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like in activity
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DOI：
10.1097/fbp.0b013e3282f62d8c
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发表时间：
2008-03-01
影响因子：
1.6
通讯作者：
Atack, John R.
中科院分区：
文献类型：
--
作者：
Galici, Ruggero;Boggs, Jamin D.;Atack, John R.
5-HT7受体与许多精神疾病有关，包括焦虑和抑郁。5-HT7受体在丘脑中的定位，以及许多非典型抗精神病药物对这些受体的高亲和力，导致了5-HT7拮抗剂在精神分裂症中的作用的推测。这些研究的目的是在预测抗精神病药样活性的动物模型中检查药物阻断和5-HT7受体基因消融的效果。我们观察了选择性5-羟色胺7受体拮抗剂SB-269970对苯丙胺和氯胺酮所致的兴奋性和脉冲前抑制缺陷的影响。此外，还评价了5-HT7基因敲除小鼠的感觉运动门控功能和运动活性。使用自动红外光束系统测量了长达180分钟的运动活动，并在惊吓室内评估了PPI。SB-269970(3、10和30 mg/kg，腹腔注射)显著阻断苯丙胺[3 mg/kg，皮下注射]。氯胺酮(30 mg/kg，皮下注射)可引起大鼠多动，苯丙胺(10 mg/kg，皮下注射)可逆转氯胺酮(30 mg/kg，皮下注射)所致的PPI缺失，但不改变自发活动和惊厥幅度。最大剂量的SB-269970不能阻断苯丙胺对5-HT7基因敲除小鼠的作用。总之，这些结果表明，阻断5-HT7受体可以部分调节谷氨酸和多巴胺能功能，并可能在临床上用于治疗精神分裂症的阳性症状。
5-HT7 receptors have been linked to a number of psychiatric disorders including anxiety and depression. The localization of 5-HT7 receptors in the thalamus, a key sensory processing center, and the high affinity of many atypical antipsychotic compounds for these receptors have led to the speculation of the utility of 5-HT7 antagonists in schizophrenia. The goal of these studies was to examine the effects of pharmacologic blockade and genetic ablation of 5-HT7 receptors in animal models predictive of antipsychotic-like activity. We evaluated the effects of SB-269970, a selective 5-HT7 receptor antagonist, on amphetamine and ketamine-induced hyperactivity and prepulse inhibition (PPI) deficits. In addition, sensorimotor gating function and locomotor activity were evaluated in 5-HT7 knockout mice. Locomotor activity was measured for up to 180 min using an automated infrared photobeam system, and PPI was evaluated in startle chambers. SB-269970 (3, 10 and 30 mg/kg, intraperitoneally) significantly blocked amphetamine [3 mg/kg, subcutaneously (s.c.)] and ketamine (30mg/kg, s.c.)-induced hyperactivity and reversed amphetamine (10mg/kg, s.c.)-induced but not ketamine (30 mg/kg, s.c.)-induced PPI deficits, without changing spontaneous locomotor activity and startle amplitude. The largest dose of SB-269970 did not block the effects of amphetamine in 5-HT7 knockout mice. Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia.