Novelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.

求新行为和冲动是与多种精神疾病（包括注意力缺陷多动障碍）相关的人格特征。潜在的神经机制仍然知之甚少。我们为zdhhc15生产并表征了一系列敲除小鼠，其编码神经棕榈酰转移酶。zdhhc15 的遗传缺陷与人类的智力障碍和行为异常有关。Zdhhc15-KO 小鼠表现出正常的空间学习和工作记忆，但在开放领域中表现出新奇诱导的运动显着增加。在适应新环境的阶段，纹状体多巴胺含量减少，但细胞外多巴胺水平增加。与对照组相比，苯丙胺和哌醋甲酯的给药导致突变小鼠腹侧纹状体的运动和细胞外多巴胺水平显着增加。黑质纹状体和中脑边缘通路中多巴胺能神经元的数量和投射正常。在纹状体中检测已知ZDHHC15基材，包括DAT的基棕榈酰化没有显著变化zdhhc15使用酰基-生物素交换试验的 KO 小鼠。这些结果支持腹侧纹状体中细胞外多巴胺的瞬时、可逆和新奇诱导的升高有助于啮齿动物的新奇行为，并暗示 ZDHHC15 介导的棕榈酰化是纹状体中多巴胺的新调节机制。