Department of Psychological Medicine and Psychiatry, Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
Int J Neuropsychopharmacol. 2011 Nov;14(10):1327-39. doi: 10.1017/S1461145711000010. Epub 2011 Feb 1.
Antipsychotic drugs are the clinical standard for the treatment of schizophrenia. Although these drugs work initially, many compliant patients relapse due to treatment failure. The known biomarkers can not sufficiently explain antipsychotic treatment failure. We, therefore, enquired how the dynamic responses of the neurotransmitters, dopamine and serotonin, change in relation to treatment action and failure. Rats received either short-term (2-6 d) or long-term (12-14 d) treatment with haloperidol, which resembled human D2 receptor occupancy, using osmotic mini-pumps. Dopamine and serotonin basal levels and responses to novelty, appetitive food, and to an aversive tail pinch were measured in the prefrontal cortex, nucleus accumbens and caudate putamen using in-vivo microdialysis, and the behaviour was recorded. Subsequently, we used in-vivo voltammetry to measure dopamine overflow in the nucleus accumbens. Haloperidol decreased dopamine, but not serotonin baseline levels in a time-dependent way. Salient stimuli induced dopamine and serotonin responses. Short-term haloperidol treatment attenuated the mesolimbic dopamine responses to aversive stimulation, while the responses to appetitive stimulation were largely preserved. After long-term treatment, the initial response adaptations were reversed. Similar changes were also observed at the behavioural level. In-vivo voltammetry showed that nucleus accumbens dopamine adaptations and their reversal were mediated by changes in extracellular dopamine release. Chronic haloperidol treatment, which resembles human D2 receptor occupancy, modulates dopamine and behavioural responses to aversive and appetitive stimulation depending on the duration of treatment. Specific changes in dopamine response dynamics and their reversal may be a functional substrate of antipsychotic action and failure respectively.
抗精神病药物是治疗精神分裂症的临床标准。尽管这些药物最初有效，但许多依从性好的患者因治疗失败而复发。已知的生物标志物不能充分解释抗精神病药物治疗失败的原因。因此，我们想了解神经递质多巴胺和血清素的动态反应如何与治疗作用和失败相关变化。使用渗透微型泵，大鼠接受短期（2-6 天）或长期（12-14 天）氟哌啶醇治疗，这类似于人类 D2 受体占据。使用在体微透析测量前额叶皮层、伏隔核和尾壳核中的多巴胺和血清素基础水平以及对新奇、食欲刺激和厌恶尾部刺痛的反应，并记录行为。随后，我们使用在体伏安法测量伏隔核中的多巴胺溢出。氟哌啶醇以时间依赖的方式降低多巴胺，但不降低血清素的基础水平。显著刺激诱导多巴胺和血清素反应。短期氟哌啶醇治疗减弱了中脑边缘多巴胺对厌恶刺激的反应，而对食欲刺激的反应则基本保留。长期治疗后，最初的反应适应被逆转。在行为水平上也观察到类似的变化。在体伏安法显示，伏隔核多巴胺的适应及其逆转是由细胞外多巴胺释放的变化介导的。类似于人类 D2 受体占据的慢性氟哌啶醇治疗，根据治疗持续时间，调节多巴胺和对厌恶和食欲刺激的行为反应。多巴胺反应动力学的特定变化及其逆转可能分别是抗精神病作用和失败的功能基础。
