Adams Wendy K, D'souza Anna M, Sussman Jacob L, Kaur Sukhbir, Kieffer Timothy J, Winstanley Catharine A
Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada; UBC Institute of Mental Health, University of British Columbia, Vancouver, BC, Canada.
Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
Physiol Behav. 2018 Aug 1;192:134-144. doi: 10.1016/j.physbeh.2018.03.027. Epub 2018 Mar 27.
Evidence suggests that impulse control deficits contribute to excessive food intake in some individuals with obesity. In addition to its known role in regulating appetite and glucose metabolism, the hormone leptin also directly modulates the activity of central dopamine systems. Although dopamine is involved in regulating impulsivity, the influence of leptin per se on this cognitive domain remains unclear. This study explored the performance of male leptin knockout (KO) and wild type (WT) rats in the 5-Choice Serial Reaction Time task (5CSRTT) of motor impulsivity and visuospatial attention. Behavioural performance was assessed under baseline conditions, following 4 weeks high-fat diet (HFD; 60 kcal%) consumption, and after acute pharmacological challenge with the indirect dopamine agonist, amphetamine. Subjects were also tested for glucose tolerance and insulin sensitivity, and dorsal and ventral striatal tissue was assayed ex vivo for markers of dopaminergic transmission. Obese KO rats learned the 5CSRTT at a slower rate compared to WT rats, in a manner suggestive of mild attentional impairment. However, task performance at baseline and after HFD intake was similar to that of WT controls. HFD intake reduced omissions across all subjects, whereas amphetamine challenge revealed a prominent genotype effect on 5CSRTT performance, with potentiated levels of impulsive responding and faster response times in KO rats compared to WT animals. Effects of amphetamine on other variables were similar between genotypes. Notably, the expression of striatal dopaminergic markers was unchanged in KO rats, and neither chronic food restriction nor HFD intake altered the impairments in glucose or insulin metabolism previously reported in these animals. These data suggest that leptin deficiency enhances impulsive action under conditions of dopaminergic challenge, yet this seems independent of overt changes in the expression of post-synaptic markers of dopamine signalling in striatal regions.
有证据表明，冲动控制缺陷会导致一些肥胖个体摄入过多食物。除了在调节食欲和葡萄糖代谢方面的已知作用外，瘦素激素还直接调节中枢多巴胺系统的活性。虽然多巴胺参与调节冲动性，但瘦素本身对这一认知领域的影响仍不清楚。本研究探讨了雄性瘦素基因敲除（KO）大鼠和野生型（WT）大鼠在运动冲动性和视觉空间注意力的5选串行反应时任务（5CSRTT）中的表现。在基线条件下、食用4周高脂饮食（HFD；60千卡%）后以及用间接多巴胺激动剂苯丙胺进行急性药物激发后，评估行为表现。还对受试者进行了葡萄糖耐量和胰岛素敏感性测试，并对背侧和腹侧纹状体组织进行离体检测，以检测多巴胺能传递的标志物。与WT大鼠相比，肥胖KO大鼠学习5CSRTT的速度较慢，提示存在轻度注意力损伤。然而，基线时和摄入HFD后的任务表现与WT对照组相似。摄入HFD减少了所有受试者的遗漏错误，而苯丙胺激发显示出对5CSRTT表现有显著的基因型效应，与WT动物相比，KO大鼠的冲动反应水平增强且反应时间更快。苯丙胺对其他变量的影响在不同基因型之间相似。值得注意的是，KO大鼠纹状体多巴胺能标志物的表达没有变化，长期食物限制和HFD摄入均未改变这些动物先前报道的葡萄糖或胰岛素代谢损伤。这些数据表明，在多巴胺能激发条件下，瘦素缺乏会增强冲动行为，但这似乎与纹状体区域多巴胺信号突触后标志物表达的明显变化无关。
