Rationale

Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia.

Objectives

This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆⁹-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors.

Methods

The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats.

Results

GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3–3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments.

Conclusion

Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.

中文翻译：

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1型大麻素受体阳性变构调节剂GAT211的抗精神病潜力：临床前体内和体外研究

基本原理

抗精神病药有助于减轻精神分裂症的积极症状；然而，它们使人衰弱的副作用促使人们寻求更好的治疗选择。可以在啮齿类动物行为模型中筛选新型化合物在神经元细胞培养物中的抗精神病潜力，以及在非竞争性拮抗剂（例如MK-801）对急性N-甲基-D-天冬氨酸（NMDA）受体阻断后进行筛选。考虑到NMDA受体和1型大麻素受体（CB1R）之间的已知相互作用，调节CB1Rs的化合物可能对精神分裂症具有治疗潜力。

目标

本研究评估是否CB1R正变构调节剂GAT211相比，Δ当⁹四氢大麻酚（THC），具有潜在减少在大鼠急性MK-801治疗精神病行为表型，和块hyperdopaminergic信令与这些行为相关联。

方法

比较了Neuro2a细胞中GAT211和THC对细胞信号传导的影响，并评估了雄性Long Evans大鼠中GAT211和THC对急性MK-801治疗引起的运动功能改变和行为惊吓响应的行为抑制作用。

结果

GAT211限制了Neuro2a细胞中多巴胺D2受体介导的细胞外调节激酶（ERK）磷酸化，而THC则没有。如预期的那样，急性MK-801（0.15 mg / kg）导致运动活动显着增加，PPI受损。单独的GAT211治疗（0.3–3.0 mg / kg）剂量依赖性地降低了运动能力和听觉惊吓反应。GAT211（3.0 mg / kg）还可以预防由MK-801引起的运动过快，但不会显着影响PPI损伤。

结论

综上所述，这些发现支持有关CB1R阳性变构调节剂作为抗精神病药的实用性的临床前研究。