Khella Ramy, Short Jennifer L, Malone Daniel T
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.
Psychopharmacology (Berl). 2014 Aug;231(16):3071-87. doi: 10.1007/s00213-014-3481-x. Epub 2014 Apr 5.
Whilst cannabinoid CB2 receptors were thought to exist predominantly in immune cells in the periphery, the recent discovery of CB2 receptors in the brain has led to an increased interest in the role of these central CB2 receptors. Several studies have reported an association with CB2 receptors and schizophrenia. Sensorimotor gating deficits occur in schizophrenia patients and can be induced in animals using psychotomimetic drugs such as N-methyl-D-aspartate (NMDA) receptor antagonists.
The aim of this study was to investigate the effect of CB2 ligands on sensorimotor gating, either alone, or on sensorimotor gating deficits induced by the NMDA receptor antagonist MK-801 in mice.
The effects of CB2 receptor ligands on prepulse inhibition (PPI), an operational measure of sensorimotor gating, alone or when administrated in combination with MK-801, in Balb-C mice were evaluated.
The CB2 receptor agonist JWH015 had no significant effect on PPI alone but reversed disruptions in PPI induced by MK-801. This effect was blocked by co-administration of the CB2 receptor antagonist AM630, but not by co-administration of the CB1 receptor antagonist AM251, indicating a CB2-mediated effect. The mixed CB1/CB2 receptor agonist JWH203 was partially able to reverse MK-801-induced PPI disruptions. Neither the CB2 receptor antagonist AM630 nor the CB1 receptor antagonist AM251 had any significant effect alone or on MK-801-induced disruptions in PPI.
CB2 receptor agonism reversed MK-801 disruptions in sensorimotor gating deficits in mice, indicating that CB2 agonism may have a protective effect against aspects of drug-induced psychosis.
虽然大麻素CB2受体被认为主要存在于外周免疫细胞中，但最近在大脑中发现CB2受体后，人们对这些中枢CB2受体的作用越来越感兴趣。几项研究报告了CB2受体与精神分裂症之间的关联。精神分裂症患者存在感觉运动门控缺陷，并且可以使用诸如N-甲基-D-天冬氨酸（NMDA）受体拮抗剂等拟精神病药物在动物中诱导出这种缺陷。
本研究的目的是研究CB2配体对感觉运动门控的影响，包括单独作用以及对NMDA受体拮抗剂MK-801诱导的小鼠感觉运动门控缺陷的影响。
评估了CB2受体配体对Balb-C小鼠的前脉冲抑制（PPI）的影响，PPI是感觉运动门控的一项操作性指标，单独使用或与MK-801联合使用时的影响。
CB2受体激动剂JWH015单独对PPI没有显著影响，但能逆转MK-801诱导的PPI破坏。CB2受体拮抗剂AM630共同给药可阻断这种作用，但CB1受体拮抗剂AM251共同给药则不能，表明这是一种由CB2介导的效应。CB1/CB2混合受体激动剂JWH203能够部分逆转MK-801诱导的PPI破坏。CB2受体拮抗剂AM630和CB1受体拮抗剂AM251单独使用或对MK-801诱导的PPI破坏均无显著影响。
CB2受体激动作用可逆转MK-801对小鼠感觉运动门控缺陷的破坏，表明CB2激动作用可能对药物诱导的精神病方面具有保护作用。
