Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats.
Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats.
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右美甲苯与组胺能和血清素能治疗的相互作用，以减少大鼠尼古丁自我给药。
DOI：
10.1016/j.pbb.2015.12.004
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Levin ED
中科院分区：
文献类型：
--
作者：
Briggs SA;Hall BJ;Wells C;Slade S;Jaskowski P;Morrison M;Rezvani AH;Rose JE;Levin ED
将有效的治疗与戒烟的不同作用机制相结合，可以通过靶向成瘾神经回路中的多个控制点来提供更好的治疗。先前在大鼠模型中的研究表明，具有α3β4烟碱和NMDA受体拮抗剂作用的美沙芬可显著减少尼古丁自我给药。我们在大鼠模型中发现，H1组胺拮抗剂吡拉明和5-羟色胺5 HT 2c激动剂氯卡色林也显著减少尼古丁自我给药。本研究旨在确定美沙芬与吡拉明和氯卡色林对大鼠尼古丁自我给药的相互作用。为年轻成年雌性大鼠配备颈静脉IV导管，并训练其自我给予0.03 mg/kg/输注剂量的尼古丁。在对美沙芬进行的初始剂量效应函数研究中，我们发现在1 - 30 mg/kg剂量范围内尼古丁自我给药单调减少，最低有效剂量为3 mg/kg。然后，在两个单独的大鼠队列中，研究了美沙芬（0、3.3和10 mg/kg）与吡拉明（0、4.43和13.3 mg/kg）的相互作用以及与氯卡色林（0、0.3125和0.625 mg/kg）的相互作用。在吡拉明-美沙芬相互作用研究中，急性剂量的吡拉明（13.3 mg/kg）以及急性剂量的美沙芬导致尼古丁自我给药显著减少。这两种药物有相互增强的作用。与单独使用10 mg/kg美沙芬（p<0.05）或单独使用13.3 mg/kg吡拉明（p <0.0005）相比，美沙芬（10 mg/kg）和吡拉明（13.3 mg/kg）的组合显著降低了尼古丁自我给药。在氯卡色林-美沙芬研究中，氯卡色林急性剂量（0.312 mg/kg）和美沙芬急性剂量（10 mg/kg）导致尼古丁自我给药显著减少，与先前的结果一致。观察到美沙芬和吡拉明以及氯卡色林的相互作用增强。这些研究结果表明，联合治疗可能是比单药治疗更有效的戒烟治疗。
Combining effective treatments with diverse mechanisms of action for smoking cessation may provide better therapy by targeting multiple points of control in the neural circuits underlying addiction. Previous research in a rat model has shown that dextromethorphan, which has α3β4 nicotinic and NMDA glutamatergic antagonist actions, significantly decreases nicotine self-administration. We have found in the rat model that the H1 histamine antagonist pyrilamine and the serotonin 5HT2c agonist lorcaserin also significantly reduce nicotine self-administration. The current studies were conducted to determine the interactive effects of dextromethorphan with pyrilamine and lorcaserin on nicotine self-administration in rats. Young adult female rats were fitted with jugular IV catheters and trained to self-administer a nicotine infusion dose of 0.03-mg/kg/infusion. In an initial dose-effect function study of dextromethorphan, we found a monotonic decrease in nicotine self-administration over a dose range of 1 to 30-mg/kg with a lowest effective dose of 3-mg/kg. Then, with two separate cohorts of rats, dextromethorphan (0, 3.3, and 10-mg/kg) interactions with pyrilamine (0, 4.43, and 13.3-mg/kg) were investigated as well as interactions with lorcaserin (0, 0.3125 and 0.625-mg/kg). In the pyrilamine-dextromethorphan interaction study, the acute dose of pyrilamine (13.3-mg/kg) as well as an acute dose of dextromethorphan caused a significant decrease in nicotine self-administration. There were mutually augmenting effects of these two drugs. The combination of dextromethorphan (10-mg/kg) and pyrilamine (13.3-mg/kg) significantly lowered nicotine self-administration relative to either 10-mg/kg of dextromethorphan alone (p<0.05) or 13.3-mg/kg of pyrilamine alone (p<0.0005). In the lorcaserin-dextromethorphan study, an acute dose of lorcaserin (0.312-mg/kg) as well as an acute dose of dextromethorphan (10-mg/kg) caused a significant decrease in nicotine self-administration replicating previous findings. Augmenting interactions were observed with dextromethorphan and pyrilamine as well as lorcaserin. These findings suggest that combination therapy may be more effective smoking cessation treatments than monotherapy.