Cortez Isadora Lopes, Silva Nicole R, Rodrigues Naielly S, Pedrazzi João Francisco C, Del Bel Elaine A, Mechoulam Raphael, Gomes Felipe V, Guimarães Francisco S
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2022 Jul 13;117:110553. doi: 10.1016/j.pnpbp.2022.110553. Epub 2022 Mar 25.
Despite attenuating the positive symptoms, drugs currently used to treat schizophrenia frequently do not improve the negative symptoms and cognitive impairments. In addition, they show low tolerability, which has been associated with high rates of treatment discontinuation. Recent evidence suggests that the endocannabinoid system may be a target for schizophrenia treatment. The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients. Here, we aimed to evaluate whether HU-910, a selective CB2 receptor agonist, would reverse schizophrenia-related behavioral changes observed after the acute injections of amphetamine or the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. We also investigated the effects of HU-910 in the memory impairment caused by repeated MK-801 administration. Finally, we tested whether HU-910 would produce the cannabinoid tetrad (catalepsy, hypolocomotion, hypothermia, and antinociception). In male C57BL/6 mice, the acute treatment with HU-910 (30 mg/kg) prevented the hyperlocomotion induced by acute MK-801. This effect was blocked by the CB2 receptor antagonist AM630 (1 mg/kg). On the contrary, HU-910 did not prevent the increased locomotor activity caused by acute amphetamine. The acute treatment with HU-910 (3, 10, and 30 mg/kg) also attenuated the impairments in the prepulse inhibition test induced by acute MK-801 and amphetamine. The repeated treatment with HU-910 attenuated the cognitive impairment caused by chronic administration of MK-801 in the novel object recognition test. Furthermore, HU-910 did not produce the cannabinoid tetrad. These results indicate that HU-910 produced antipsychotic-like effects and support further research on the potential therapeutic properties of this compound to treat schizophrenia.
尽管目前用于治疗精神分裂症的药物能减轻阳性症状，但往往无法改善阴性症状和认知障碍。此外，这些药物耐受性较低，这与高停药率相关。最近有证据表明，内源性大麻素系统可能是治疗精神分裂症的一个靶点。CB2受体调节多巴胺能神经传递，而精神分裂症患者的多巴胺能神经传递异常增强。在此，我们旨在评估选择性CB2受体激动剂HU - 910是否能逆转在急性注射苯丙胺或N - 甲基 - D - 天冬氨酸受体（NMDAR）拮抗剂MK - 801后观察到的与精神分裂症相关的行为变化。我们还研究了HU - 910对重复给予MK - 801所导致的记忆损伤的影响。最后，我们测试了HU - 910是否会产生大麻素四联征（僵住、运动减少、体温过低和抗伤害感受）。在雄性C57BL / 6小鼠中，HU - 910（30毫克/千克）急性处理可预防急性MK - 801诱导的运动亢进。这种作用被CB2受体拮抗剂AM630（1毫克/千克）阻断。相反，HU - 910不能预防急性苯丙胺引起的运动活性增加。HU - 910（3、10和30毫克/千克）急性处理也减轻了急性MK - 801和苯丙胺诱导的前脉冲抑制试验中的损伤。HU - 910重复处理减轻了慢性给予MK - 801在新物体识别试验中引起的认知损伤。此外，HU - 910未产生大麻素四联征。这些结果表明，HU - 910产生了类似抗精神病的作用，并支持对该化合物治疗精神分裂症潜在治疗特性的进一步研究。
