Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
Yukon University, Whitehorse, YT, Y1A 5K4, Canada.
Psychopharmacology (Berl). 2021 Apr;238(4):1087-1098. doi: 10.1007/s00213-020-05755-x. Epub 2021 Jan 13.
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.
This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors.
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.
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.
Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.
抗精神病药有助于缓解精神分裂症相关的阳性症状；然而，其使人虚弱的副作用促使人们寻求更好的治疗选择。可以在神经元细胞培养物中筛选新型化合物，以评估其抗精神病潜力，并在啮齿动物行为模型中使用非竞争性 NMDA 受体拮抗剂（如 MK-801）急性阻断 NMDA 受体后进行筛选。鉴于 NMDA 受体和 1 型大麻素受体（CB1R）之间的已知相互作用，调节 CB1R 的化合物可能具有治疗精神分裂症的潜力。
本研究评估了与 ∆-四氢大麻酚（THC）相比，CB1R 正变构调节剂 GAT211 在急性 MK-801 治疗后是否具有减轻大鼠精神病行为表型的潜力，并阻断与这些行为相关的过度多巴胺能信号。
比较了 GAT211 和 THC 对 Neuro2a 细胞中细胞信号的影响，并在雄性长耳大鼠中评估了 GAT211 和 THC 对急性 MK-801 治疗引起的运动活动改变和声刺激起始反应的前脉冲抑制的行为影响。
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（0.15mg/kg）导致运动活动显著增加和 PPI 受损。GAT211 单独治疗（0.3-3.0mg/kg）剂量依赖性地降低运动活动和听觉起始反应。GAT211（3.0mg/kg）还可预防 MK-801 引起的过度运动，但对 PPI 损伤无显著影响。
这些发现支持继续进行关于 CB1R 正变构调节剂作为抗精神病药的有用性的临床前研究。
