Further pharmacological characterization of 5-HT2C receptor agonist-induced inhibition of 5-HT neuronal activity in the dorsal raphe nucleus in vivo
Further pharmacological characterization of 5-HT2C receptor agonist-induced inhibition of 5-HT neuronal activity in the dorsal raphe nucleus in vivo
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DOI：
10.1111/j.1476-5381.2009.00406.x
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发表时间：
2009-11-01
影响因子：
7.3
通讯作者：
Sharp, T.
中科院分区：
文献类型：
--
作者：
Queree, P.;Peters, S.;Sharp, T.
背景与目的：最近使用非选择性5-羟色胺（5-HT）（2C）受体激动剂（包括WAY 161503）进行的实验表明，中脑5-HT神经元受5-HT2C受体的抑制控制，通过邻近的γ -氨基丁酸（GABA）神经元起作用。本研究通过比较WAY 161503与5-HT2C受体激动剂，Ro 60-0275和1-（3-氯苯基）哌嗪（mCPP），以及非选择性5-HT激动剂麦角酸二乙胺（LSD）和5-HT释放剂3,4-亚甲基二氧甲基苯丙胺（MDMA）的作用，扩展了这一药理特性。实验方法：采用细胞外记录法测定麻醉大鼠中缝背核（DRN） 5-HT神经元活动。采用双标记免疫组化法测定Fos和谷氨酸脱羧酶（GAD），评估DRN - GABA神经元的活性。关键结果：Ro 60-0175与WAY 161503一样，抑制5-HT神经元放电，而5-HT2C拮抗剂SB 242084逆转了这一作用。mCPP还以SB 242084可逆的方式抑制5-HT神经元的放电（类似于60%的神经元）。LSD抑制5-HT神经元放电；然而，SB 242084或5-HT2A/C受体拮抗剂利坦色林均未改变这种作用，但5-HT1A受体拮抗剂WAY 100635可逆转这种作用。同样，MDMA抑制5-HT神经元放电的方式可被WAY 100635逆转，但SB 242084或利坦色林则不能。最后，Ro 60-0275和mCPP与WAY 161503一样，增加了gad阳性DRN神经元中Fos的表达。结论和意义：这些数据加强了中脑5-HT神经元受5-HT2C受体抑制控制的假设，并表明5-HT2C激动剂Ro 60-0175， mCPP和WAY 161503，而不是LSD或MDMA，是所涉及机制的有用探针。
Background and purpose:Recent experiments using non-selective 5-hydroxytryptamine (5-HT)(2C) receptor agonists including WAY 161503 suggested that midbrain 5-HT neurones are under the inhibitory control of 5-HT2C receptors, acting via neighbouring gamma-aminobutyric acid (GABA) neurones. The present study extended this pharmacological characterization by comparing the actions of WAY 161503 with the 5-HT2C receptor agonists, Ro 60-0275 and 1-(3-chlorophenyl) piperazine (mCPP), as well as the non-selective 5-HT agonist lysergic acid diethylamide (LSD) and the 5-HT releasing agent 3,4-methylenedioxymethamphetamine (MDMA).Experimental approach:5-HT neuronal activity was measured in the dorsal raphe nucleus (DRN) using extracellular recordings in anaesthetized rats. The activity of DRN GABA neurones was assessed using double-label immunohistochemical measurements of Fos and glutamate decarboxylase (GAD).Key results:Ro 60-0175, like WAY 161503, inhibited 5-HT neurone firing, and the 5-HT2C antagonist SB 242084 reversed this effect. mCPP also inhibited 5-HT neurone firing (similar to 60% neurones) in a SB 242084-reversible manner. LSD inhibited 5-HT neurone firing; however, this effect was not altered by either SB 242084 or the 5-HT2A/C receptor antagonist ritanserin but was reversed by the 5-HT1A receptor antagonist WAY 100635. Similarly, MDMA inhibited 5-HT neurone firing in a manner reversible by WAY 100635, but not SB 242084 or ritanserin. Finally, both Ro 60-0275 and mCPP, like WAY 161503, increased Fos expression in GAD-positive DRN neurones.Conclusions and implications:These data strengthen the hypothesis that midbrain 5-HT neurones are under the inhibitory control of 5-HT2C receptors, and suggest that the 5-HT2C agonists Ro 60-0175, mCPP and WAY 161503, but not LSD or MDMA, are useful probes of the mechanism(s) involved.