Iman Ismail Nurul, Ahmad Nur Aimi Zawami, Mohd Yusof Nurul Aiman, Talib Ummi Nasrah, Norazit Anwar, Kumar Jaya, Mehat Muhammad Zulfadli, Hassan Zurina, Müller Christian P, Muzaimi Mustapha
Department of Neurosciences, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.
Department of Anatomy, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kota Bharu, Malaysia.
Front Pharmacol. 2021 Sep 16;12:708055. doi: 10.3389/fphar.2021.708055. eCollection 2021.
Kratom is a widely abused plant-based drug preparation with a global interest in recent years, well beyond its native grounds in Southeast Asia. Mitragynine, its major psychoactive constituent is known to exhibit opioid-like behavioral effects with resultant neuroplasticity in the brain reward system. Its chronic administration is associated with cognitive impairments in animal studies. However, the underlying molecular mechanism for such a deficit remains elusive. In this study, the involvement of cannabinoid type-1 (CB) receptors in cognitive deficits after chronic mitragynine exposures was investigated for 28 days (with incremental dose sensitization from 1 to 25 mg/kg) in adult male Swiss albino mice using the IntelliCage system. Chronic high-dose mitragynine exposure (5-25 mg/kg, intraperitoneal [i.p.]), but not low-dose exposure (1-4 mg/kg, i.p.), induced hyperlocomotion, potentiated the preference for sucrose reward, increased resistance to punishment, and impaired place learning and its reversal. Comparable deficits were also observed after chronic treatments with Δ-9-tetrahydrocannabinol (THC, 2 mg/kg, i.p.) or morphine (5 mg/kg, subcutaneous). Mitragynine-, morphine-, and THC-induced learning and memory deficits were reversed by co-treatment with the CB receptor antagonist, NIDA-41020 (10 mg/kg, i.p.). A significant upregulation of CB receptor expression was found in the hippocampal CA1 region and ventral tegmental area after chronic high-dose mitragynine and morphine, whereas a downregulation was observed after chronic THC. In conclusion, the present study suggests a plausible role of the CB receptor in mediating the dose-dependent cognitive deficits after chronic high-dose mitragynine exposure. This also highlights the potential of CB receptor antagonism in ameliorating the cognitive deficits associated with long-term kratom/mitragynine consumption in humans.
kratom是一种近年来在全球范围内受到广泛滥用的植物性药物制剂，其受关注程度已远超其原产东南亚地区。其主要精神活性成分——帽柱木碱已知具有类阿片样行为效应，并会在大脑奖赏系统中产生神经可塑性。在动物研究中，长期服用该药物与认知障碍有关。然而，导致这种缺陷的潜在分子机制仍不清楚。在本研究中，利用智能笼系统，对成年雄性瑞士白化小鼠进行了为期28天（剂量从1mg/kg递增至25mg/kg并产生剂量敏感性）的慢性帽柱木碱暴露实验，以研究1型大麻素（CB）受体在慢性帽柱木碱暴露后认知缺陷中的作用。慢性高剂量帽柱木碱暴露（5 - 25mg/kg，腹腔注射[i.p.]），而非低剂量暴露（1 - 4mg/kg，腹腔注射），会诱发运动亢进，增强对蔗糖奖赏的偏好，增加对惩罚的抵抗力，并损害位置学习及其逆转。在用Δ-9-四氢大麻酚（THC，2mg/kg，腹腔注射）或吗啡（5mg/kg，皮下注射）进行慢性治疗后，也观察到了类似的缺陷。帽柱木碱、吗啡和THC诱导的学习和记忆缺陷可通过与CB受体拮抗剂NIDA-41020（10mg/kg，腹腔注射）联合治疗得到逆转。在慢性高剂量帽柱木碱和吗啡处理后，海马CA1区和腹侧被盖区的CB受体表达显著上调，而在慢性THC处理后则观察到下调。总之，本研究表明CB受体在介导慢性高剂量帽柱木碱暴露后的剂量依赖性认知缺陷中可能发挥作用。这也凸显了CB受体拮抗剂在改善与人类长期服用kratom/帽柱木碱相关的认知缺陷方面的潜力。
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