Poulia Nafsika, Delis Foteini, Brakatselos Charalampos, Ntoulas George, Asprogerakas Michail-Zois, Antoniou Katerina
Department of Pharmacology, University of Ioannina, Ioannina, Greece.
Front Pharmacol. 2021 Oct 27;12:746935. doi: 10.3389/fphar.2021.746935. eCollection 2021.
Clinical evidence and experimental studies have shown the psychotomimetic properties induced by ketamine. Moreover, acute or chronic ketamine (KET) administration has been widely used for modeling schizophrenia-like symptomatology and pathophysiology. Several studies have reported the antipsychotic potential of cannabidiol (CBD), while there is limited information on the cannabidiol effect on KET-induced schizophrenia-like impairments. Therefore, the goal of the present study was to evaluate neuroplastic changes induced by repeated KET administration, which is used as an experimental model of schizophrenia-with a behavioral focus on positive-like symptomatology- and to assess the modulatory role of CBD treatment. The present findings have shown a robust increase in motor activity in KET-treated rats, following a 10-day period of chronic administration at the sub-anesthetic dose of 30 mg/kg (i.p), that was reversed to normal by subsequent chronic CBD treatment. Concerning the expression of glutamate receptors, the current findings have shown region-dependent KET-induced constitutional alterations in NMDA and AMPA receptors that were modified by subsequent CBD treatment. Additionally, repeated KET administration increased ERK1/2 phosphorylation state in all regions examined, apart from the ventral hippocampus that was modulated by subsequent CBD treatment. The present results show, for the first time, a stimulated motor output coupled with a specific glutamatergic-related status and ERK1/2 activation following chronic KET administration that were attenuated by CBD treatment, in a region-dependent manner. These findings provide novel information concerning the antipsychotic potential of CBD using a specific design of chronic KET administration, thus contributing to experimental approaches that mirror the symptomatology and pathophysiology of schizophrenia.
临床证据和实验研究表明，氯胺酮具有拟精神病特性。此外，急性或慢性给予氯胺酮（KET）已被广泛用于模拟精神分裂症样症状和病理生理学。多项研究报道了大麻二酚（CBD）的抗精神病潜力，而关于CBD对KET诱导的精神分裂症样损伤影响的信息有限。因此，本研究的目的是评估重复给予KET诱导的神经可塑性变化（将KET用作精神分裂症的实验模型，重点关注阳性样症状的行为表现），并评估CBD治疗的调节作用。目前的研究结果表明，在以30mg/kg（腹腔注射）的亚麻醉剂量进行10天的慢性给药后，KET处理的大鼠运动活动显著增加，随后的慢性CBD治疗可使其恢复正常。关于谷氨酸受体的表达，目前的研究结果表明，KET诱导的NMDA和AMPA受体的区域依赖性结构改变可被随后的CBD治疗所改变。此外，重复给予KET可增加所有检测区域的ERK1/2磷酸化状态，但腹侧海马体除外，随后的CBD治疗可对其进行调节。本研究结果首次表明，慢性给予KET后，运动输出受到刺激，同时伴有特定的谷氨酸能相关状态和ERK1/2激活，而CBD治疗以区域依赖性方式减弱了这些作用。这些发现通过慢性KET给药的特定设计提供了关于CBD抗精神病潜力的新信息，从而有助于反映精神分裂症症状和病理生理学的实验方法。
