PPAR Agonists: II. Fenofibrate and Tesaglitazar Alter Behaviors Related to Voluntary Alcohol Consumption
PPAR Agonists: II. Fenofibrate and Tesaglitazar Alter Behaviors Related to Voluntary Alcohol Consumption
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DOI：
10.1111/acer.12972
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发表时间：
2016-03-01
影响因子：
3.2
通讯作者：
Harris, R. Adron
中科院分区：
文献类型：
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作者：
Blednov, Yuri A.;Black, Mendy;Harris, R. Adron
在随后的文章中，我们发现非诺贝特和替格列他激活过氧化物酶体增殖物激活受体α (PPAR)信号传导可降低小鼠乙醇（EtOH）消耗。在这项研究中，我们确定了这些PPAR激动剂在EtOH相关行为和其他可能对调节EtOH消耗很重要的行为中的作用。方法观察非诺贝特（150mg/kg）和替格列他（1.5mg/kg）对雄性和雌性C57BL/6J （B6）和B6x129S4小鼠糖精偏好、EtOH诱导的条件位置偏好（CPP）、条件味觉厌恶（CTA）、转直反射丧失和戒断、声惊反射、新事物反应和EtOH清除的影响。由于B6近交系通常表现出弱etoh诱导的CPP和弱etoh诱导的急性戒断反应，我们也对B6x129S4小鼠进行了研究。结果非诺贝特和替格列他降低了新反应，增加了急性EtOH戒断严重程度，非诺贝特增加了EtOH诱导的CTA。非诺贝特和替格列他没有改变EtOH消耗的两个重要因素（糖精偏好和EtOH诱导的CPP）。非诺贝特和替格列他均能提高EtOH清除率。对新奇事物的反应、急性戒断和EtOH清除显示出性别差异，这可能有助于非诺贝特治疗后EtOH消耗的减少。这些研究表明，PPAR激动剂改变了etoh依赖性和etoh非依赖性行为的复杂性，并为这些药物的新行为作用提供了证据，这些行为作用可能有助于PPAR介导的饮酒作用。
Background In the accompanying article, we showed that activation of peroxisome proliferator-activated receptor alpha (PPAR) signaling by fenofibrate and tesaglitazar decreases ethanol (EtOH) consumption in mice. In this study, we determined the role of these PPAR agonists in EtOH-related behaviors and other actions that may be important in regulating EtOH consumption.Methods The effects of fenofibrate (150mg/kg) and tesaglitazar (1.5mg/kg) were examined on the following responses in male and female C57BL/6J (B6) and B6x129S4 mice: preference for saccharin, EtOH-induced conditioned place preference (CPP), conditioned taste aversion (CTA), loss of righting reflex, and withdrawal, acoustic startle reflex, response to novelty, and EtOH clearance. Because the B6 inbred strain usually displays weak EtOH-induced CPP and weak EtOH-induced acute withdrawal, B6x129S4 mice were also studied.Results Fenofibrate and tesaglitazar decreased the novelty response and increased acute EtOH withdrawal severity, and fenofibrate increased EtOH-induced CTA. Two important factors for EtOH consumption (saccharin preference and EtOH-induced CPP) were not altered by fenofibrate or tesaglitazar. EtOH clearance was increased by both fenofibrate and tesaglitazar. Response to novelty, acute withdrawal, and EtOH clearance show sex differences and could contribute to the reduced EtOH consumption following fenofibrate administration.Conclusions These studies indicate the complexity of EtOH-dependent and EtOH-independent behaviors that are altered by PPAR agonists and provide evidence for novel behavioral actions of these drugs that may contribute to PPAR-mediated effects on alcohol drinking.