Fan Zhang, Katherine L Nicholson, Keith L Shelton, Todd M Hillhouse, Herbert Y Meltzer, Joseph H Porter
{"title":"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","authors":"Fan Zhang, Katherine L Nicholson, Keith L Shelton, Todd M Hillhouse, Herbert Y Meltzer, Joseph H Porter","doi":"10.1097/FBP.0000000000000834","DOIUrl":null,"url":null,"abstract":"<p><p>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(Belviq) is a serotonin 5-HT2C agonist that was previously marketed as a weight-loss medication but was voluntarily withdrawn from the market because of a small, but an increased risk of serious side effects.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.</p>","PeriodicalId":8832,"journal":{"name":"Behavioural Pharmacology","volume":" ","pages":""},"PeriodicalIF":1.6000,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Role of serotonin 5HT2C receptors in the discriminative stimulus properties of lorcaserin in male C57BL/6 mice.\",\"authors\":\"Fan Zhang, Katherine L Nicholson, Keith L Shelton, Todd M Hillhouse, Herbert Y Meltzer, Joseph H Porter\",\"doi\":\"10.1097/FBP.0000000000000834\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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Role of serotonin 5HT2C receptors in the discriminative stimulus properties of lorcaserin in male C57BL/6 mice.
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.
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.