Chronic methamphetamine (METH) treatment induces behavioral sensitization in rodents. During this process, hyperactivation of the mesolimbic dopamine system plays a central role, and dopamine D2-like receptor-based antipsychotics are known to alleviate the behavioral hyperactivity. The atypical antipsychotic, clozapine (Clz), acts partially as a dopamine D4 receptor (D4R) antagonist and mitigates hyperdopaminergic drug addiction and/or comorbid psychotic symptoms; however, it remains unclear whether D4R blockade contributes to the therapeutic effects of Clz. Here, we evaluated the potential role of D4R in regulating hyperdopaminergia-induced behavioral hyperactivity in METH behavioral sensitization and dopamine transporter (DAT) knockdown (KD) mice. Clz or a D4R-selective antagonist, L-745,870, were co-administered to mice with daily METH in a METH sensitization model, and Clz or L-745,870 were administered alone in a DAT KD hyperactivity model. Locomotor activity and accumbal D4R expression were analyzed. Clz suppressed both the initiation and expression of METH behavioral sensitization, as well as DAT KD hyperactivity. However, repetitive Clz treatment induced tolerance to the suppression effect on METH sensitization initiation. In contrast, D4R inhibition by L-745,870 had no effect on METH sensitization or DAT KD hyperactivity. Accumbal D4R expression was similar between METH-sensitized mice with and without Clz co-treatment. In sum, our results suggest the mesolimbic D4R does not participate in behavioral sensitization encoded by hyperdopaminergia, a finding which likely extends to the therapeutic effects of Clz. Therefore, molecular targets other than D4R should be prioritized in the development of future therapeutics for treatment of hyperdopaminergia-dependent neuropsychiatric disorders.

慢性甲基苯丙胺 (METH) 治疗会引起啮齿动物的行为致敏。在此过程中，中脑边缘多巴胺系统的过度激活起着核心作用，已知基于多巴胺 D2 受体的抗精神病药可缓解行为过度活跃。非典型抗精神病药氯氮平 (Clz) 部分充当多巴胺 D4 受体 (D4R) 拮抗剂并减轻高多巴胺能药物成瘾和/或合并精神病症状；然而，目前尚不清楚 D4R 阻断是否有助于 Clz 的治疗效果。在这里，我们评估了 D4R 在调节 METH 行为敏化和多巴胺转运蛋白 (DAT) 敲低 (KD) 小鼠中多巴胺能诱发的行为过度活跃中的潜在作用。Clz 或 D4R 选择性拮抗剂，L-745,870，在 METH 致敏模型中将每日 METH 与小鼠共同给药，并在 DAT KD 多动症模型中单独给药 Clz 或 L-745,870。分析了运动活动和累积的 D4R 表达。Clz 抑制 METH 行为敏化的启动和表达，以及 DAT KD 过度活跃。然而，重复的 Clz 处理诱导了对 METH 致敏起始的抑制作用的耐受性。相比之下，L-745,870 对 D4R 的抑制对 METH 致敏或 DAT KD 过度活跃没有影响。Accumbal D4R 表达在有和没有 Clz 共同治疗的 METH 致敏小鼠之间相似。总之，我们的结果表明中脑边缘 D4R 不参与由多巴胺能亢进编码的行为敏化，这一发现可能扩展到 Clz 的治疗效果。所以，