Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Department of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo 183-0042, Japan.
Int J Mol Sci. 2022 Jul 4;23(13):7436. doi: 10.3390/ijms23137436.
Some diseases that are associated with dopamine deficiency are accompanied by psychiatric symptoms, including Parkinson's disease. However, the mechanism by which this occurs has not been clarified. Previous studies found that dopamine-deficient (DD) mice exhibited hyperactivity in a novel environment. This hyperactivity is improved by clozapine and donepezil, which are used to treat psychiatric symptoms associated with dopamine deficiency (PSDD). We considered that DD mice could be used to study PSDD. In the present study, we sought to identify the pharmacological mechanism of PSDD. We conducted locomotor activity tests by administering quetiapine and drugs that have specific actions on serotonin (5-hydroxytryptamine [5-HT]) receptors and muscarinic receptors. Changes in neuronal activity that were induced by drug administration in DD mice were evaluated by examining Fos immunoreactivity. Quetiapine suppressed hyperactivity in DD mice while the 5-HT receptor antagonist WAY100635 inhibited this effect. The number of Fos-positive neurons in the median raphe nucleus increased in DD mice that exhibited hyperactivity and was decreased by treatment with quetiapine and 5-HT receptor agonists. In conclusion, hyperactivity in DD mice was ameliorated by quetiapine, likely through 5-HT receptor activation. These findings suggest that 5-HT receptors may play a role in PSDD, and 5-HT receptor-targeting drugs may help improve PSDD.
一些与多巴胺缺乏相关的疾病伴有精神症状，包括帕金森病。然而，其发生的机制尚未阐明。先前的研究发现，多巴胺缺乏（DD）小鼠在新环境中表现出过度活跃。这种过度活跃可以通过氯氮平和多奈哌齐改善，它们用于治疗与多巴胺缺乏相关的精神症状（PSDD）。我们认为 DD 小鼠可用于研究 PSDD。在本研究中，我们试图确定 PSDD 的药理学机制。我们通过给予喹硫平和对 5-羟色胺（5-HT）受体和毒蕈碱受体具有特定作用的药物来进行运动活性测试。通过检查 Fos 免疫反应性来评估药物给药后 DD 小鼠中诱导的神经元活性变化。喹硫平抑制 DD 小鼠的过度活跃，而 5-HT 受体拮抗剂 WAY100635 抑制了这种作用。在表现出过度活跃的 DD 小鼠中，中缝核的 Fos 阳性神经元数量增加，而用喹硫平和 5-HT 受体激动剂治疗则减少了这些神经元数量。总之，DD 小鼠的过度活跃通过 5-HT 受体激活得到改善。这些发现表明 5-HT 受体可能在 PSDD 中发挥作用，5-HT 受体靶向药物可能有助于改善 PSDD。
