The human cannabinoid receptor 2 (CB2R) gene CNR2 has been associated with schizophrenia development. Inbred mice treated with the CB2R inverse agonist AM630 and challenged with methamphetamine (MAP) showed reduced prepulse inhibition (%PPI) response and locomotor hyperactivity, both behavioral measures in rodents that correlate with psychosis. Mice lacking CB2R on striatal dopaminergic neurons exhibit a hyperdopaminergic tone and a hyperactivity phenotype. Hyperdopaminergia plays a role in the etiology of schizophrenia. This study aimed to determine the direct role of CB2R, heterozygous Cnr2 gene knockout (Het) mice treated with MAP to induce behavioral sensitivity mimicking a schizophrenia-like human phenotype. Additionally, the study aims to explore the unique modulation of dopamine activity by neuronal CB2R. Conditional knockout DAT-Cnr2^−/− mice were evaluated in response to MAP treatments for this purpose. Sensorimotor gating deficits in DAT-Cnr2^−/− mice were also evaluated. Het mice developed reverse tolerance (RT) to MAP-enhanced locomotor activity, and RT reduced the %PPI compared to wild-type (WT) mice. DAT-Cnr2^−/− mice showed an increased sensitivity to stereotypical behavior induced by MAP and developed RT to MAP. DAT-Cnr2^−/− mice exhibit a reduction in %PPI and alter social interaction, another core symptom of schizophrenia. These results demonstrate that there is an interaction between neuronal CB2R and MAP treatment, which increases the risk of schizophrenia-like behavior in this mouse model. This finding provides evidence for further studies targeting CB2R as a potential schizophrenia therapy.

人类大麻素受体 2 (CB2R) 基因CNR2与精神分裂症的发展有关。用 CB2R反向激动剂AM630治疗并用甲基苯丙胺 (MAP) 攻击的近交小鼠表现出前脉冲抑制 (%PPI) 反应降低和运动过度活跃，这两种行为指标均与精神病相关。纹状体多巴胺能神经元上缺乏 CB2R 的小鼠表现出多巴胺能亢进和多动表型。多巴胺能亢进在精神分裂症的病因学中发挥着重要作用。本研究旨在确定用 MAP 治疗的 CB2R（杂合Cnr2基因敲除 (Het) 小鼠）诱导模仿精神分裂症样人类表型的行为敏感性的直接作用。此外，该研究旨在探索神经元 CB2R 对多巴胺活性的独特调节。为此目的，评估了条件性敲除 DAT- Cnr2 ^−/−小鼠对 MAP 治疗的反应。还评估了DAT- Cnr2 ^{−/−小鼠的感觉运动门控缺陷。}Het 小鼠对 MAP 增强的运动活动产生反向耐受性 (RT)，与野生型 (WT) 小鼠相比，RT 降低了 %PPI。DAT- Cnr2 ^−/−小鼠对 MAP 诱导的刻板行为表现出更高的敏感性，并发展出针对 MAP 的 RT。DAT- Cnr2 ^−/−小鼠表现出 %PPI 降低并改变社交互动，这是精神分裂症的另一个核心症状。这些结果表明，神经元 CB2R 和 MAP 治疗之间存在相互作用，这增加了该小鼠模型中精神分裂症样行为的风险。这一发现为进一步研究将 CB2R 作为潜在的精神分裂症疗法提供了证据。