Gill Kathryn M, Cook James M, Poe Michael M, Grace Anthony A
*To whom correspondence should be addressed; Department of Neuroscience, University of Pittsburgh, A210 Langley Hall, Pittsburgh, PA 15260, US; tel: 1-412-624-7332, fax: 1-412-624-9198, e-mail:
Schizophr Bull. 2014 Mar;40(2):341-50. doi: 10.1093/schbul/sbt236. Epub 2014 Jan 24.
Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long-term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel α5 gamma-aminobutyric acid (GABA(A)) receptor positive allosteric modulator (α5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6 mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both α5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to α5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective.
尽管已知长期使用抗精神病药物治疗会使多巴胺（DA）系统发生变化，但新型化合物治疗精神分裂症的试验通常是在患者短暂停用正在使用的药物后进行测试的。本研究探讨了从重复使用氟哌啶醇（HAL）治疗中撤药的影响，以及对新型α5γ-氨基丁酸（GABA(A)）受体正向变构调节剂（α5PAM）的反应，对精神分裂症甲基氮杂氧甲醇醋酸酯（MAM）神经发育模型中DA系统活性的影响。在从重复使用HAL（21天，0.6mg/kg，口服）撤药7天后，对MAM和生理盐水（SAL）大鼠腹侧被盖区的DA神经元进行电生理记录。在单独的动物中，测量苯丙胺诱导的运动，以评估DA行为敏感性的变化。从HAL撤药的SAL大鼠表现出自发性DA神经元活动减少，同时对苯丙胺的运动反应增强，这表明DA超敏反应的发展。α5PAM治疗和腹侧海马（vHPC）失活均逆转了SAL大鼠HAL撤药后的DA神经元去极化阻滞。相比之下，与未治疗的SAL大鼠相比，从HAL撤药的MAM大鼠表现出自发性DA活动减少，对苯丙胺的运动反应增强；然而，这种情况对α5PAM治疗或vHPC失活无反应。先前HAL治疗的撤药会干扰这种新型治疗在精神分裂症MAM模型中的治疗作用。因此，在长期治疗的精神分裂症患者身上测试新型化合物可能无效。
