National Clinical Research Center for Mental Disorders, and Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
Affiliated Mental Health Centre & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310013, China.
Transl Psychiatry. 2024 Feb 6;14(1):79. doi: 10.1038/s41398-024-02800-7.
The brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between negative symptoms of schizophrenia and high fasting blood glucose. We then show that glucose metabolism and negative symptoms are improved when intermittent theta burst stimulation (iTBS) on prefrontal cortex (PFC) is performed in patients with predominantly negative symptoms of schizophrenia. These findings led us to hypothesize that the prefrontal cortical dopamine deficit, which is known to be associated with negative symptoms, may be responsible for abnormal glucose metabolism in schizophrenia. To explore this, we optogenetically and chemogenetically inhibited the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine projection in mice and found both procedures caused glucose intolerance. Moreover, microinjection of dopamine two receptor (D2R) neuron antagonists into mPFC in mice significantly impaired glucose tolerance. Finally, a transgenic mouse model of psychosis named Disc1 exhibited depressive-like symptoms, impaired glucose homeostasis, and compared to wild type littermates reduced D2R expression in prefrontal cortex.
大脑神经递质多巴胺可能在调节全身葡萄糖稳态中发挥重要作用。在 704 名首次发作精神分裂症的未经药物治疗的患者中，我们提供了有力的证据表明精神分裂症的阴性症状与空腹高血糖之间存在正相关。然后我们表明，当在以阴性症状为主的精神分裂症患者的前额叶皮层（PFC）上进行间歇性 theta 爆发刺激（iTBS）时，葡萄糖代谢和阴性症状得到改善。这些发现使我们假设，已知与阴性症状相关的前额叶皮质多巴胺缺乏可能是精神分裂症中葡萄糖代谢异常的原因。为了探讨这一点，我们通过光遗传学和化学遗传学抑制了小鼠腹侧被盖区（VTA）-内侧前额叶皮层（mPFC）多巴胺投射，发现这两种方法都导致葡萄糖不耐受。此外，将多巴胺 2 型受体（D2R）神经元拮抗剂微注射到小鼠的 mPFC 中会显著损害葡萄糖耐量。最后，一种名为 Disc1 的精神分裂症转基因小鼠模型表现出抑郁样症状、葡萄糖稳态受损，与野生型同窝仔相比，前额叶皮层中的 D2R 表达减少。
