Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys
Repeated 7-Day Treatment with the 5-HT2C Agonist Lorcaserin or the 5-HT2A Antagonist Pimavanserin Alone or in Combination Fails to Reduce Cocaine vs Food Choice in Male Rhesus Monkeys
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DOI：
10.1038/npp.2016.259
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发表时间：
2017-04-01
影响因子：
7.6
通讯作者：
Negus, S. Stevens
中科院分区：
文献类型：
--
作者：
Banks, Matthew L.;Negus, S. Stevens
可卡因使用障碍是一个全球性的公共卫生问题，目前还没有食品和药物管理局批准的药物治疗方法。新出现的临床前证据表明，5-羟色胺（5-HT） 2C和2A受体是介导5-羟色胺能衰减可卡因滥用相关神经化学和行为效应的潜在机制。因此，本研究的目的是确定恒河猴在同时选择可卡因和食物供应的情况下，5-HT2C激动剂氯卡色林（0.1-1.0 mg/kg/天，肌肉注射；0.0320.1 mg/kg/h，静脉注射）或5-HT2A逆激动剂/拮抗剂匹马万色林（0.32-10 mg/kg/天，肌肉注射）重复治疗7天是否会减弱可卡因强化。在生理盐水治疗期间，可卡因与食物选择保持剂量依赖性的增加。重复使用匹马万色林（每天3.2 mg/kg）显著增加了小单位可卡因剂量的选择。大剂量的氯卡色林（每天1.0 mg/kg和每天0.1 mg/kg/h）和匹马万色林（每天10 mg/kg）主要降低了手术行为率。同时使用无效的氯卡色林（每天0.1毫克/公斤）和匹马万色林（每天0.32毫克/公斤）也不能显著改变可卡因的选择。这些结果表明，5-HT2C受体激活和5-HT2A受体阻断都不足以产生治疗样的可卡因选择减少和食物选择的补充增加。总的来说，这些结果不支持5-HT2C激动剂和5-HT2A逆激动剂/拮抗剂单独或联合作为抗可卡因使用障碍药物治疗的候选药物的临床应用。
Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT2C agonist lorcaserin (0.1-1.0 mg/kg per day, intramuscular; 0.0320.1 mg/kg/h, intravenous) or the 5-HT2A inverse agonist/antagonist pimavanserin (0.32-10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent ' choice ' schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT2C receptor activation nor 5-HT2A receptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT2C agonists and 5-HT2A inverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.