Role of serotonin 5HT2C receptors in the discriminative stimulus properties of lorcaserin in male C57BL/6 mice.

IF 1.6 4区 心理学 Q3 BEHAVIORAL SCIENCES
Fan Zhang, Katherine L Nicholson, Keith L Shelton, Todd M Hillhouse, Herbert Y Meltzer, Joseph H Porter
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引用次数: 0

Abstract

The serotonin 2C receptor (5-HT2C) has been investigated as a potential therapeutic target for a variety of psychiatric disorders, as well as the treatment of obesity. A stumbling block in the development of these medications is identifying agonists with selectivity for 5-HT2C over 5-HT2A and 5-HT2B. Lorcaserin (Belviq) is a serotonin 5-HT2C agonist that was previously marketed as a weight-loss medication but was voluntarily withdrawn from the market because of a small, but an increased risk of serious side effects. The present study examined the discriminative stimulus properties of 2.0 mg/kg lorcaserin in a two-lever drug discrimination assay in male C57BL/6 mice using a fixed ratio 12 reinforcement schedule. A generalization curve with lorcaserin yielded an effective dose50 (ED50) = 0.56 mg/kg for substitution for the training dose. Lorcaserin produced a rapid onset, but short-acting (~60 min), discriminative stimulus, as full generalization was found as early as 15 min after drug administration. The 5-HT2C agonist meta-chlorophenylpiperazine fully substituted for lorcaserin with an ED50 = 0.31 mg/kg, and the 5-HT2C antagonist SB 242084 significantly blocked lorcaserin-lever responding (maximal effect at 0.25 mg/kg dose). Conversely, the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin did not substitute for lorcaserin. Thus, lorcaserin's discriminative stimulus appears to be mediated by agonist activity at 5HT2C receptors in C57BL/6 mice. These results demonstrated that lorcaserin drug discrimination can be trained in C57BL/6 mice and that it is a useful in-vivo assay for the future development of psychotherapeutic drugs for psychiatric disorders with selective 5-HT2C agonist activity.

5 -羟色胺5HT2C受体在雄性C57BL/6小鼠氯卡色胺鉴别刺激特性中的作用
5-羟色胺2C受体(5-HT2C)已被研究为多种精神疾病以及肥胖治疗的潜在治疗靶点。开发这些药物的一个障碍是确定对5-HT2C比5-HT2A和5-HT2B具有选择性的激动剂。Lorcaserin (Belviq)是一种5-羟色胺5-HT2C激动剂,曾作为减肥药上市,但由于副作用虽小,但风险增加,因此自愿退出市场。本研究采用双水平药物鉴别试验,采用固定比例12强化方案,研究2.0 mg/kg氯卡色林对雄性C57BL/6小鼠的鉴别刺激特性。氯卡色林的泛化曲线显示,替代训练剂量的有效剂量50 (ED50) = 0.56 mg/kg。氯卡色林产生起效快但作用短(约60分钟)的判别性刺激,早在给药后15分钟即发现完全泛化。5-HT2C激动剂间氯苯哌嗪完全取代氯卡西林,ED50 = 0.31 mg/kg, 5-HT2C拮抗剂SB 242084显著阻断氯卡西林水平应答(剂量为0.25 mg/kg时效果最大)。相反,5-HT1A激动剂8-羟基-2-(二正丙基氨基)四萘林不能替代氯卡色林。因此,氯卡色林的特异性刺激似乎是由C57BL/6小鼠5HT2C受体的激动剂活性介导的。这些结果表明,氯卡色林在C57BL/6小鼠身上的药物识别是可以训练的,这为未来开发具有选择性5-HT2C激动剂活性的精神疾病心理治疗药物提供了一种有用的体内实验方法。
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来源期刊
Behavioural Pharmacology
Behavioural Pharmacology 医学-行为科学
CiteScore
3.40
自引率
0.00%
发文量
84
审稿时长
6-12 weeks
期刊介绍: Behavioural Pharmacology accepts original full and short research reports in diverse areas ranging from ethopharmacology to the pharmacology of schedule-controlled operant behaviour, provided that their primary focus is behavioural. Suitable topics include drug, chemical and hormonal effects on behaviour, the neurochemical mechanisms under-lying behaviour, and behavioural methods for the study of drug action. Both animal and human studies are welcome; however, studies reporting neurochemical data should have a predominantly behavioural focus, and human studies should not consist exclusively of clinical trials or case reports. Preference is given to studies that demonstrate and develop the potential of behavioural methods, and to papers reporting findings of direct relevance to clinical problems. Papers making a significant theoretical contribution are particularly welcome and, where possible and merited, space is made available for authors to explore fully the theoretical implications of their findings. Reviews of an area of the literature or at an appropriate stage in the development of an author’s own work are welcome. Commentaries in areas of current interest are also considered for publication, as are Reviews and Commentaries in areas outside behavioural pharmacology, but of importance and interest to behavioural pharmacologists. Behavioural Pharmacology publishes frequent Special Issues on current hot topics. The editors welcome correspondence about whether a paper in preparation might be suitable for inclusion in a Special Issue.
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