Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan.
Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan.
Pharmacol Biochem Behav. 2021 Dec;211:173288. doi: 10.1016/j.pbb.2021.173288. Epub 2021 Oct 13.
The excessive blockade of dopamine D2 receptors (DRD2s) with long-term antipsychotic treatment is known to induce a dopamine supersensitivity state (DSS). The mechanism of DSS is speculated to be a compensatory up-regulation of DRD2s, but an excess blockade of DRD2s can also cause glutamatergic neuronal damage. Herein, we investigated whether antipsychotic-induced neuronal damage plays a role in the development of DSS.
Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSS rats and non-DSS rats based on their voluntary locomotion data. We then determined the tissue levels of glutamate transporter-1 (GLT-1)/glutamine synthetase (GS) and heat shock protein-70 (HSP-70) in the rats' brain regions.
The levels of HSP-70 in the striatum and CA-3 region of the DSS rats were significantly higher than those of the control and non-DSS rats, whereas the dentate gyrus HSP-70 levels in both the DSS and non-DSS rats were increased versus the controls. The levels of GLT-1/GS in the CA-3 and nucleus accumbens were increased in the DSS rats.
These results suggest that the DSS rats experienced striatal neuronal damage and indicate that a HAL-induced upregulation of HSP-70 and the GLT-1/GS system in the CA3 may be involved in the development of DSS. It remains unknown why the non-DSS rats did not suffer neuronal damage. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, dopamine supersensitivity psychosis, and tardive dyskinesia, further investigations of our findings are warranted.
长期使用抗精神病药物治疗会过度阻断多巴胺 D2 受体（DRD2s），从而导致多巴胺超敏状态（DSS）。DSS 的机制推测是 DRD2s 的代偿性上调，但 DRD2s 的过度阻断也会导致谷氨酸能神经元损伤。在此，我们研究了抗精神病药诱导的神经元损伤是否在 DSS 的发展中起作用。
通过渗透微型泵向大鼠给予氟哌啶醇（HAL；每天 0.75mg/kg，共 14 天）或载体。根据 HAL 处理大鼠的自发运动数据，将其分为 DSS 大鼠和非 DSS 大鼠组。然后，我们测定了大鼠脑区谷氨酸转运体-1（GLT-1）/谷氨酰胺合成酶（GS）和热休克蛋白-70（HSP-70）的组织水平。
DSS 大鼠纹状体和 CA-3 区的 HSP-70 水平明显高于对照组和非 DSS 大鼠，而 DSS 和非 DSS 大鼠的齿状回 HSP-70 水平均高于对照组。DSS 大鼠 CA-3 和伏隔核的 GLT-1/GS 水平增加。
这些结果表明 DSS 大鼠经历了纹状体神经元损伤，表明 HAL 诱导的 HSP-70 和 CA3 中的 GLT-1/GS 系统上调可能参与了 DSS 的发展。非 DSS 大鼠为何没有遭受神经元损伤尚不清楚。鉴于需要针对治疗抵抗性精神分裂症、多巴胺超敏性精神病和迟发性运动障碍的治疗策略，有必要进一步研究我们的发现。
