Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, 92697-4540, USA.
Psychopharmacology (Berl). 2011 Apr;214(4):843-53. doi: 10.1007/s00213-010-2091-5. Epub 2010 Nov 19.
Cognitive deficits are common in schizophrenia. Asenapine is an atypical antipsychotic approved by the US Food and Drug Administration in adults for treatment of schizophrenia or acute treatment, as monotherapy or adjunct therapy to lithium or valproate, of manic or mixed episodes of bipolar I disorder.
Based on the receptor pharmacology of asenapine, the current study assessed the efficacy and mechanism of action of asenapine to improve a subchronic phencyclidine (PCP)-induced deficit in visual recognition memory using the novel object recognition (NOR) paradigm in the rat, a paradigm of relevance to cognition in schizophrenia.
Female-hooded Lister rats received vehicle or PCP (2 mg/kg, i.p.) for 7 days, followed by a 7-day washout. On the test day, rats were given asenapine (0.001-0.1 mg/kg, s.c.) alone or in combination with the D(1) receptor antagonist SCH-23390 (0.05 mg/kg, i.p.) or 5-HT(1A) receptor antagonist WAY100635 (1 mg/kg, i.p.). Time spent exploring two identical objects during a 3-min acquisition trial (followed by a 1-min intertrial interval) and then a familiar and a novel object for another 3 min (retention trial) were recorded onto videotape and scored blind.
In the retention trial, vehicle- but not PCP-treated animals explored the novel object significantly more than the familiar object (p < 0.001). Asenapine (0.01-0.075 mg/kg) reversed PCP-induced deficits in NOR (p < 0.01-0.001) in a dose-related manner. This effect was antagonised by SCH-23390 but not by WAY100635.
These results demonstrate a role for D(1) but not 5-HT(1A) receptor mechanisms in mediating the cognitive effects of asenapine in this rodent model.
认知缺陷在精神分裂症中很常见。阿塞那平是一种非典型抗精神病药物，已获美国食品和药物管理局批准，可用于治疗精神分裂症，或作为锂盐或丙戊酸盐的辅助治疗，用于双相情感障碍 I 型躁狂或混合发作的急性治疗。
基于阿塞那平的受体药理学，本研究采用新颖物体识别（NOR）范式评估了阿塞那平改善亚慢性苯环己哌啶（PCP）诱导的大鼠视觉识别记忆缺陷的疗效和作用机制，该范式与精神分裂症的认知相关。
雌性 Hooded Lister 大鼠接受 vehicle 或 PCP（2mg/kg，ip）连续 7 天，然后进行 7 天的洗脱期。在测试日，大鼠单独给予阿塞那平（0.001-0.1mg/kg，sc）或与 D1 受体拮抗剂 SCH-23390（0.05mg/kg，ip）或 5-HT1A 受体拮抗剂 WAY100635（1mg/kg，ip）联合给药。在 3 分钟的获得试验（随后是 1 分钟的试验间隔）中，记录大鼠花费在探索两个相同物体上的时间，然后是 3 分钟的熟悉和新物体的保留试验。将录像带记录下来并进行盲法评分。
在保留试验中，与 vehicle 处理的动物相比，PCP 处理的动物明显更多地探索新物体（p < 0.001）。阿塞那平（0.01-0.075mg/kg）以剂量相关的方式逆转了 PCP 诱导的 NOR 缺陷（p < 0.01-0.001）。该作用被 SCH-23390 拮抗，但不被 WAY100635 拮抗。
这些结果表明，D1 受体机制而不是 5-HT1A 受体机制在介导阿塞那平在该啮齿动物模型中的认知作用。
