Anxiolytic effects of buspirone and MTEP in the Porsolt Forced Swim Test.
Anxiolytic effects of buspirone and MTEP in the Porsolt Forced Swim Test.
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DOI：
10.1177/2470547017712985
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发表时间：
2017-01
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影响因子：
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通讯作者：
Szumlinski KK
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文献类型：
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作者：
Lee KM;Coelho MA;Sern KR;Class MA;Bocz MD;Szumlinski KK
传统上，Porsolt强迫游泳试验中漂浮行为或不动能力的减少被用作抗抑郁疗效的预测指标。然而，在过去的几年里，我们对酒精戒断引起的负面情绪的研究一直表明，在各种行为测试中，焦虑相关行为的增加与强迫游泳测试中的不动减少是一致的。此外，这种行为特征与边缘脑区mGlu5蛋白表达增加有关。由于mGlu5在焦虑中的作用已经确立，我们假设，在强迫游泳测试中，酒精戒断小鼠表现出的不动减少可能反映了焦虑，可能是对急性游泳应激源的高反应性。在这里，我们评估了酒精戒断期间减少的强迫游泳试验不动是否对行为有效剂量的典型抗焦虑药物丁螺环酮(5 mg/kg)的全身治疗有反应。我们还通过比较丁螺环酮和mGlu5负性变构调节剂MTEP(3 mg/kg)的行为有效剂量，确定了戒断诱导的mGlu5表达增加与强迫游泳测试行为的功能相关性。成年雄性C57BL/6J小鼠接受14天、多瓶、狂饮的方案，在戒断早期引起高度焦虑并增加谷氨酸相关蛋白的表达。对照组动物只喝水。停药24小时后，每种饮水条件下的动物被分成不同的组，在强迫游泳试验前30 分钟，给予丁螺环酮、MTEP或赋形剂进行治疗。药物对一般运动活动的影响也被评估。正如我们之前所报道的，与水对照组相比，酒精戒断的动物在强迫游泳测试中表现出显著的静止减少。丁螺环酮和MTEP都显著增加了酒精戒断动物的不动能力，在水控制方面也有轻微的增加。两组患者的运动能力没有显著差异，表明两种抗焦虑药物都没有镇静作用。这些结果为强迫游泳试验中游泳增加/不动减少作为焦虑模型提供了预测有效性，并为mGlu5抑制作为治疗酒精戒断期间高焦虑的有效治疗策略提供了新的证据。
Traditionally, a reduction in floating behavior or immobility in the Porsolt forced swim test is employed as a predictor of anti-depressant efficacy. However, over the past several years, our studies of alcohol withdrawal-induced negative affect consistently indicate the coincidence of increased anxiety-related behaviors on various behavioral tests with reduced immobility in the forced swim test. Further, this behavioral profile correlates with increased mGlu5 protein expression within limbic brain regions. As the role for mGlu5 in anxiety is well established, we hypothesized that the reduced immobility exhibited by alcohol-withdrawn mice when tested in the forced swim test might reflect anxiety, possibly a hyper-reactivity to the acute swim stressor. Herein, we evaluated whether or not the decreased forced swim test immobility during alcohol withdrawal responds to systemic treatment with a behaviorally effective dose of the prototypical anxiolytic, buspirone (5 mg/kg). We also determined the functional relevance of the withdrawal-induced increase in mGlu5 expression for forced swim test behavior by comparing the effects of buspirone to a behaviorally effective dose of the mGlu5 negative allosteric modulator MTEP (3 mg/kg). Adult male C57BL/6J mice were subjected to a 14-day, multi-bottle, binge-drinking protocol that elicits hyper-anxiety and increases glutamate-related protein expression during early withdrawal. Control animals received only water. At 24-h withdrawal, animals from each drinking condition were subdivided into groups and treated with an intraperitoneal injection of buspirone, MTEP, or vehicle, 30 min prior to the forced swim test. Drug effects on general locomotor activity were also assessed. As we reported previously, alcohol-withdrawn animals exhibited significantly reduced immobility in the forced swim test compared to water controls. Both buspirone and MTEP significantly increased immobility in alcohol-withdrawn animals, with a modest increase also seen in water controls. No significant group differences were observed for locomotor activity, indicating that neither anxiolytic was sedating. These results provide predictive validity for increased swimming/reduced immobility in the forced swim test as a model of anxiety and provide novel evidence in favor of mGlu5 inhibition as an effective therapeutic strategy for treating hyper-anxiety during alcohol withdrawal.