Choy Kwok H C, Shackleford David M, Malone Daniel T, Mistry Shailesh N, Patil Rahul T, Scammells Peter J, Langmead Christopher J, Pantelis Christos, Sexton Patrick M, Lane Johnathan R, Christopoulos Arthur
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.).
Drug Discovery Biology (K.H.C.C., D.T.M, C.J.L, P.M.S, J.R.L, A.C.), Centre for Drug Candidate Optimization (D.M.S., R.T.P.), and Medicinal Chemistry (S.N.M, P.J.S.), Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia; and Melbourne Neuropsychiatry Centre, Department of Psychiatry and Centre for Neural Engineering, University of Melbourne, Melbourne, Australia (C.P.)
J Pharmacol Exp Ther. 2016 Nov;359(2):354-365. doi: 10.1124/jpet.116.235788. Epub 2016 Sep 14.
Current antipsychotics are effective in treating the positive symptoms associated with schizophrenia, but they remain suboptimal in targeting cognitive dysfunction. Recent studies have suggested that positive allosteric modulation of the M muscarinic acetylcholine receptor (mAChR) may provide a novel means of improving cognition. However, very little is known about the potential of combination therapies in extending coverage across schizophrenic symptom domains. This study investigated the effect of the M mAChR positive allosteric modulator BQCA [1-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid], alone or in combination with haloperidol (a first-generation antipsychotic), clozapine (a second-generation atypical antipsychotic), or aripiprazole (a third-generation atypical antipsychotic), in reversing deficits in sensorimotor gating and spatial memory induced by the N-methyl-d-aspartate receptor antagonist, MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]. Sensorimotor gating and spatial memory induction are two models that represent aspects of schizophrenia modeled in rodents. In prepulse inhibition (an operational measure of sensorimotor gating), BQCA alone had minimal effects but exhibited different levels of efficacy in reversing MK-801-induced prepulse inhibition disruptions when combined with a subeffective dose of each of the three (currently prescribed) antipsychotics. Furthermore, the combined effect of BQCA and clozapine was absent in M mice. Interestingly, although BQCA alone had no effect in reversing MK-801-induced memory impairments in a Y-maze spatial test, we observed a reversal upon the combination of BQCA with atypical antipsychotics, but not with haloperidol. These findings provide proof of concept that a judicious combination of existing antipsychotics with a selective M mAChR positive allosteric modulator can extend antipsychotic efficacy in glutamatergic deficit models of behavior.
目前的抗精神病药物在治疗与精神分裂症相关的阳性症状方面有效，但在针对认知功能障碍方面仍不理想。最近的研究表明，对M型毒蕈碱乙酰胆碱受体（mAChR）进行正向变构调节可能提供一种改善认知的新方法。然而，对于联合疗法在扩展对精神分裂症症状领域的覆盖范围方面的潜力知之甚少。本研究调查了M型mAChR正向变构调节剂BQCA [1-(4-甲氧基苄基)-4-氧代-1,4-二氢喹啉-3-羧酸]单独使用或与氟哌啶醇（第一代抗精神病药物）、氯氮平（第二代非典型抗精神病药物）或阿立哌唑（第三代非典型抗精神病药物）联合使用时，对N-甲基-D-天冬氨酸受体拮抗剂MK-801 [(5R,10S)-(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺]诱导的感觉运动门控和空间记忆缺陷的逆转作用。感觉运动门控和空间记忆诱导是代表在啮齿动物中建模的精神分裂症方面的两种模型。在预脉冲抑制（感觉运动门控的一种操作测量）中，单独使用BQCA效果甚微，但与三种（目前处方的）抗精神病药物的亚有效剂量联合使用时，在逆转MK-801诱导的预脉冲抑制破坏方面表现出不同程度的疗效。此外，在M型小鼠中，BQCA和氯氮平的联合作用不存在。有趣的是，尽管单独使用BQCA在Y迷宫空间测试中对逆转MK-801诱导的记忆损伤没有作用，但我们观察到BQCA与非典型抗精神病药物联合使用时会出现逆转，而与氟哌啶醇联合使用则不会。这些发现提供了概念验证，即现有抗精神病药物与选择性M型mAChR正向变构调节剂的明智组合可以在谷氨酸能行为缺陷模型中扩展抗精神病疗效。
