Suppr超能文献

抗精神病药诱导的大鼠多巴胺超敏反应的多巴胺能机制。

Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats.

机构信息

Department of Neurosciences, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit boulevard, Montreal, H3T 1J4, Quebec, Canada.

Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, 2900 Edouard-Montpetit boulevard, Montreal, H3T 1J4, Quebec, Canada.

出版信息

Neuropharmacology. 2021 Oct 1;197:108747. doi: 10.1016/j.neuropharm.2021.108747. Epub 2021 Aug 5.

Abstract

Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d-amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d-amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d-amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d-amphetamine into the cerebral ventricles triggered the expression of already established dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity.

摘要

抗精神病药物治疗可产生多巴胺超敏状态,增强多巴胺受体刺激的反应。在精神分裂症患者和大鼠中,这与对持续抗精神病药物治疗的耐受有关。在啮齿动物中,抗精神病药物暴露停止后,多巴胺超敏通常通过 d-苯丙胺引起的精神运动反应过度来确认。在这里,我们在大鼠中检查了介导这种增强行为反应的多巴胺能机制,因为这可能揭示了抗精神病药物引起的多巴胺超敏表达背后的病理生理过程。大鼠接受 0.5mg/kg/天的氟哌啶醇通过渗透迷你泵治疗 2 周,然后停止治疗。抗精神病药物治疗停止后,大鼠对 D2 激动剂喹吡罗表现出超敏精神运动反应,但对 D1 部分激动剂 SKF38393 或多巴胺再摄取阻滞剂 GBR12783 没有反应。此外,急性 D1 受体阻断(使用 SCH39166)降低了氟哌啶醇预处理大鼠中 d-苯丙胺的过度精神运动反应,而急性 D2 受体阻断(使用舒必利)增强了该反应。因此,抗精神病药物治疗停止后,D1 和 D2 介导的传递差异调节了对 d-苯丙胺的超敏反应的表达。这种超敏行为反应伴随着伏隔核(而非尾壳核)中 GSK3β 活性的增强和 ERK1/2 活性的抑制,表明中边缘多巴胺传递增加。最后,在停止氟哌啶醇治疗后,增加腹侧中脑多巴胺冲动流或将 d-苯丙胺注入脑室均不能引发已经建立的多巴胺超敏反应的表达,这表明需要外周效应。因此,虽然多巴胺受体介导的信号转导调节抗精神病药物引起的多巴胺超敏反应的表达,但中枢多巴胺神经传递的简单增加不足以触发这种超敏反应。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验