Department of Neuroscience, Faculty of Medicine, Université de Montréal, Canada.
Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Canada.
Neuropharmacology. 2017 Sep 1;123:10-21. doi: 10.1016/j.neuropharm.2017.05.015. Epub 2017 May 15.
Long-term exposure to antipsychotics like haloperidol can increase sensitivity to dopamine agonist stimulation. This could contribute to treatment failure and increase relapse to psychosis. Chronic antipsychotic treatment elevates neurotensin levels in the nucleus accumbens (NAc), where the neuropeptide modulates dopamine function by signalling through NTS1 receptors. We hypothesized that increasing neurotensin activity in the NAc attenuates the expression of antipsychotic-induced dopamine supersensitivity, which is indicated by a potentiated psychomotor response to amphetamine. Rats received either continuous (CONT-HAL; achieved via subcutaneous osmotic minipump) or intermittent (INT-HAL; achieved via daily subcutaneous injection) haloperidol treatment for 16-17 days. Three to 5 days later, we injected neurotensin into the NAc and measured amphetamine-induced locomotion. Only CONT-HAL rats showed potentiated amphetamine-induced locomotion, indicating dopamine supersensitivity. Compared to intra-NAc saline, intra-NAc neurotensin suppressed amphetamine-induced locomotion in CONT-HAL rats, but not in INT-HAL or control rats. In a new cohort of CONT-HAL and INT-HAL rats, we measured striatal levels of proneurotensin mRNA and NTS1 receptors. The two treatments led to overlapping but also distinct neurochemical profiles. Neither treatment altered NTS1 receptor levels in the NAc, but both increased proneurotensin mRNA levels in the NAc core. In the caudate-putamen, only INT-HAL increased NTS1 receptor levels, while only CONT-HAL increased proneurotensin mRNA expression. Thus, antipsychotic-induced dopamine supersensitivity enhances the ability of neurotensin in the NAc to regulate dopamine-mediated behaviours, and this likely does not involve changes in local levels of NTS1 receptors or proneurotensin mRNA. We conclude that increasing neurotensin activity could be considered to attenuate antipsychotic-induced dopamine supersensitivity.
长期暴露于氟哌啶醇等抗精神病药物会增加对多巴胺激动剂刺激的敏感性。这可能导致治疗失败并增加精神病复发的风险。慢性抗精神病药物治疗会升高伏隔核（NAc）中的神经降压素水平，神经降压素通过 NTS1 受体信号传递来调节多巴胺功能。我们假设增加 NAc 中的神经降压素活性可以减轻抗精神病药物引起的多巴胺超敏性的表达，这种超敏性表现为对安非他命的精神运动反应增强。大鼠接受连续（CONT-HAL；通过皮下渗透微量泵实现）或间歇性（INT-HAL；通过每日皮下注射实现）氟哌啶醇治疗 16-17 天。3-5 天后，我们将神经降压素注射到 NAc 中，并测量安非他命引起的运动。只有 CONT-HAL 大鼠表现出增强的安非他命引起的运动，表明多巴胺超敏性。与 NAc 内生理盐水相比，CONT-HAL 大鼠的 NAc 内神经降压素抑制了安非他命引起的运动，但在 INT-HAL 或对照大鼠中则没有。在一组新的 CONT-HAL 和 INT-HAL 大鼠中，我们测量了纹状体中前神经降压素 mRNA 和 NTS1 受体的水平。两种处理方法导致了重叠但也不同的神经化学特征。两种处理方法都没有改变 NAc 中的 NTS1 受体水平，但都增加了 NAc 核心中的前神经降压素 mRNA 水平。在尾壳核-苍白球中，只有 INT-HAL 增加了 NTS1 受体水平，而只有 CONT-HAL 增加了前神经降压素 mRNA 的表达。因此，抗精神病药物引起的多巴胺超敏性增强了 NAc 中神经降压素调节多巴胺介导行为的能力，而这可能不涉及 NTS1 受体或前神经降压素 mRNA 的局部水平变化。我们得出结论，增加神经降压素活性可以被认为是减轻抗精神病药物引起的多巴胺超敏性。
