5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice
5-HT2C Agonists Modulate Schizophrenia-Like Behaviors in Mice
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DOI：
10.1038/npp.2017.52
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发表时间：
2017-10-01
影响因子：
7.6
通讯作者：
Wetsel, William C.
中科院分区：
文献类型：
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作者：
Pogorelov, Vladimir M.;Rodriguiz, Ramona M.;Wetsel, William C.
所有FDA批准的抗精神病药物（APD）主要靶向多巴胺D-2或5-羟色胺（5-HT 2A）受体或两者;然而，这些药物并不普遍有效，它们可能产生不良副作用，并且仅部分改善阴性和认知症状。精神分裂症患者药理学反应的异质性表明，其他药物靶点可能有效地改善这种综合征的各个方面。最近的证据表明，5-HT 2C受体可能是精神分裂症的一个有希望的靶点，因为它们的激活减少了中脑边缘黑质纹状体多巴胺的释放（传递抗精神病作用），它们几乎只在CNS中表达，并具有减肥促进能力。开发5-HT 2C激动剂的困难在于大多数配体还具有5-HT 2B和/或5-HT 2A活性。我们已经开发了选择性5-HT 2C配体，并在此描述了其治疗精神分裂症样行为的临床前有效性。JJ-3-45、JJ-3-42和JJ-5-34减少了安非他明刺激的过度运动，恢复了安非他明破坏的前脉冲抑制，改善了NMDA受体功能减退的NR 1敲除小鼠的社会行为和新物体识别记忆，并且基本上没有僵硬症。然而，它们在断点试验中降低了动机，并且没有促进MK-801处理小鼠的逆转学习。氯卡色林（一种具有强效5-HT 2B和5-HT 2A激动剂活性的5-HT 2C激动剂，已被批准用于治疗肥胖症）也观察到了类似的效果。微透析研究表明，JJ-3-42和氯卡色林都减少了边缘下皮层中的多巴胺流出，而只有JJ-3-42减少了纹状体中的多巴胺流出。总的来说，这些结果提供了额外的证据，5-HT 2C受体是合适的药物靶点，与目前的APD相比，具有更少的副作用，更大的治疗选择性和更高的治疗精神分裂症和相关疾病的疗效。
All FDA-approved antipsychotic drugs (APDs) target primarily dopamine D-2 or serotonin (5-HT2A) receptors, or both; however, these medications are not universally effective, they may produce undesirable side effects, and provide only partial amelioration of negative and cognitive symptoms. The heterogeneity of pharmacological responses in schizophrenic patients suggests that additional drug targets may be effective in improving aspects of this syndrome. Recent evidence suggests that 5-HT2C receptors may be a promising target for schizophrenia since their activation reduces mesolimbic nigrostriatal dopamine release (which conveys antipsychotic action), they are expressed almost exclusively in CNS, and have weight-loss-promoting capabilities. A difficulty in developing 5-HT2C agonists is that most ligands also possess 5-HT2B and/or 5-HT2A activities. We have developed selective 5-HT2C ligands and herein describe their preclinical effectiveness for treating schizophrenia-like behaviors. JJ-3-45, JJ-3-42, and JJ-5-34 reduced amphetamine-stimulated hyperlocomotion, restored amphetamine-disrupted prepulse inhibition, improved social behavior, and novel object recognition memory in NMDA receptor hypofunctioning NR1-knockdown mice, and were essentially devoid of catalepsy. However, they decreased motivation in a breakpoint assay and did not promote reversal learning in MK-801-treated mice. Somewhat similar effects were observed with lorcaserin, a 5-HT2C agonist with potent 5-HT2B and 5-HT2A agonist activities, which is approved for treating obesity. Microdialysis studies revealed that both JJ-3-42 and lorcaserin reduced dopamine efflux in the infralimbic cortex, while only JJ-3-42 decreased it in striatum. Collectively, these results provide additional evidence that 5-HT2C receptors are suitable drug targets with fewer side effects, greater therapeutic selectivity, and enhanced efficacy for treating schizophrenia and related disorders than current APDs.