Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada.
J Psychopharmacol. 2021 Jan;35(1):65-77. doi: 10.1177/0269881120965908. Epub 2020 Dec 4.
The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear.
Here we tested whether the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats.
We designed a HAL analog compound (HAL-F), which lacks the accumulation property of HAL, but retains its postsynaptic inhibitory action on dopamine D2 receptors.
RESULTS/OUTCOMES: By perfusing LysoTracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an amphetamine hypersensitization psychosis-like model in rats, we found that subchronic intracerebroventricularly delivered HAL (0.1 mg/kg/day), but not HAL-F (0.3-1.5 mg/kg/day), attenuates psychotic-like behavior in rats.
CONCLUSIONS/INTERPRETATION: These findings suggest the presynaptic accumulation of HAL may serve as an essential prerequisite for its full antipsychotic action and may explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action.
抗精神病药物（APD）的治疗效果主要归因于其对多巴胺 D2 受体的突触后抑制作用，但这并不能解释其完全治疗效果的延迟出现。先前的研究表明，APD 在慢性治疗期间会在突触前囊泡中积累，并以活动依赖的方式像神经递质一样释放，触发自动抑制反馈机制。尽管与治疗作用的起始非常相似，但 APD 积累过程的功能后果仍不清楚。
本研究旨在测试抗精神病药氟哌啶醇（HAL）的积累是否是精神样大鼠完全治疗作用所必需的。
我们设计了一种 HAL 类似物化合物（HAL-F），它缺乏 HAL 的积累特性，但保留了其对多巴胺 D2 受体的突触后抑制作用。
结果/结论：通过用 LysoTracker 荧光染料标记培养的海马神经元进行灌流，我们证实了 HAL 的积累和 HAL-F 的非积累。在大鼠安非他命超敏性精神样模型中，我们发现鞘内给予亚慢性 HAL（0.1mg/kg/天），而不是 HAL-F（0.3-1.5mg/kg/天），可减轻大鼠的精神样行为。
这些发现表明 HAL 的突触前积累可能是其完全抗精神病作用的必要前提，并且可以解释 APD 作用的时间过程。因此，针对 APD 积累特性可能成为改善 APD 作用的新策略。
