The serotonin 5-HT2A receptor agonist TCB-2: a behavioral and neurophysiological analysis
The serotonin 5-HT2A receptor agonist TCB-2: a behavioral and neurophysiological analysis
复制标题
DOI：
10.1007/s00213-009-1694-1
复制
发表时间：
2010-09-01
影响因子：
3.4
通讯作者：
Murphy, Dennis L.
中科院分区：
文献类型：
--
作者：
Fox, Meredith A.;French, Helen T.;Murphy, Dennis L.
关于高亲和力5-HT2A激动剂（4-溴-3,6-二甲氧基苯并环丁烯-1-基）氢溴甲烷胺（TCB-2）的报道很少。在这里，我们提供了C57BL/6J小鼠TCB-2的第一个行为和神经生理特征，并直接比较了5-HT2A/2C激动剂(+/-)-2,5-二甲氧基-4-碘苯基-2-氨基丙烷（DOI），以及通过选择性5-HT2A拮抗剂MDL 11,939预处理确定5-HT2A的调解作用。以剂量依赖的方式，TCB-2诱导头抽搐，减少食物剥夺小鼠的食物消耗，诱导体温过低和皮质酮水平升高，但对运动活动或开放领域的焦虑样行为没有影响。在与DOI的平行剂量反应比较中观察到类似的效果；与DOI相比，尽管在最高剂量（5.0 mg/kg）下，TCB-2引起的头抽搐明显减少，并显著增强了体温过低反应。MDL 11939预处理阻断TCB-2和DOI后的头抽搐和温度变化，证实5-HT2A介导了这些反应。虽然MDL 11939预处理阻断了doi诱导的摄食抑制，但MDL 11939对tcb -2诱导的摄食抑制没有影响。先前的研究表明5-HT2A的功能会随着血清素转运体（SERT）表达和功能的改变而改变。在SERT敲除（-/-）小鼠中，与SERT野生型（+/+）小鼠相比，tcb -2诱导的头抽搐和体温过低大大减少。目前的研究很重要，因为它们是第一个评估TCB-2对小鼠的影响的研究，也是第一个报道这种构象受限的苯乙胺类似化合物的行为和神经生理影响的研究，它对通过磷酸肌苷途径的信号传导的影响比花生四烯酸途径大65倍。
There are few reports on the high-affinity 5-HT2A agonist (4-Bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).Here we provide the first behavioral and neurophysiological profile of TCB-2 in C57BL/6J mice, with direct comparisons to the 5-HT2A/2C agonist (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), in addition to determinations of 5-HT2A mediation via pretreatment with the selective 5-HT2A antagonist MDL 11,939.In a dose-dependent manner, TCB-2 induced head twitches, decreased food consumption in food-deprived mice, induced hypothermia, and increased corticosterone levels, with no effects on locomotor activity or anxiety-like behaviors in the open field. Similar effects were observed in side-by-side dose-response comparisons with DOI; although at the highest dose tested (5.0 mg/kg), TCB-2 induced significantly fewer head twitches, and a significantly enhanced hypothermic response, versus DOI. Pretreatment with MDL 11,939 blocked head twitches and temperature change following TCB-2 and DOI, confirming 5-HT2A mediation of these responses. Although MDL 11,939 pretreatment blocked DOI-induced suppression of feeding, MDL 11,939 had no effect on TCB-2-induced suppression of feeding. Previous studies show that 5-HT2A function is altered by changes in serotonin transporter (SERT) expression and function. In SERT knockout (-/-) mice, TCB-2-induced head twitches and hypothermia were greatly diminished compared to SERT wild-type (+/+) mice.The current studies are important, as they are the first to assess the effects of TCB-2 in mice, and are among the first to report the behavioral and neurophysiological effects of this conformationally restricted phenethylamine analog compound, which has 65-fold greater effects on signaling via the phosphoinositide versus arachidonic acid pathways.