Szabo S T, Blier P
Neurobiological Psychiatry Unit, McGill University, Montréal, Quebec, Canada H3A 1A1.
Brain Res. 2001 Dec 13;922(1):9-20. doi: 10.1016/s0006-8993(01)03121-3.
Previous studies, using in vivo extracellular unitary recordings in anaesthetized rats, have shown that the selective 5-HT(1A) receptor antagonist WAY 100,635 suppressed the firing rate of locus coeruleus (LC) norepinephrine (NE) neurons and that this effect was abolished by lesioning 5-HT neurons. In the present experiments, the selective 5-HT(2A) receptor antagonist MDL 100,907, while having no effect on the spontaneous firing activity of LC neurons in controls, was able to restore NE neuronal discharges following the injection of WAY 100,635. The 5-HT(1A) receptor agonist 8-OH-DPAT enhanced the firing activity of NE neurons and this action was entirely dependent on intact 5-HT neurons, unlike the inhibitory effect of the 5-HT(2) receptor agonist DOI. Taken together, these data indicate that 5-HT(2A) but not 5-HT(1A) receptors controlling LC firing activity are postsynaptic to 5-HT neurons. Prolonged, but not subacute, administration of selective 5-HT reuptake inhibitors (SSRIs) produces a decrease in the spontaneous firing activity of LC NE neurons. MDL 100,907 partially reversed this suppressed firing activity of LC neurons in paroxetine-treated rats. Although the alpha(2)-adrenoceptor antagonist idazoxan also enhanced the firing activity of NE neurons in paroxetine-treated rats, this increase was similar to that obtained in controls. In conclusion, prolonged SSRI treatment enhances a tonic inhibitory influence by 5-HT on LC neurons through postsynaptic 5-HT(2A) receptors that are not located on NE neurons. A speculative neuronal circuitry accounting for these phenomena on LC NE activity is proposed.
以往利用麻醉大鼠体内细胞外单位记录的研究表明，选择性5-羟色胺（5-HT）1A受体拮抗剂WAY 100,635可抑制蓝斑（LC）去甲肾上腺素（NE）能神经元的放电频率，且损毁5-HT能神经元可消除该效应。在本实验中，选择性5-HT2A受体拮抗剂MDL 100,907对对照组LC神经元的自发放电活动无影响，但能在注射WAY 100,635后恢复NE能神经元的放电。5-HT1A受体激动剂8-OH-DPAT增强NE能神经元的放电活动，且该作用完全依赖于完整的5-HT能神经元，这与5-HT2受体激动剂DOI的抑制作用不同。综上所述，这些数据表明，控制LC放电活动的是5-HT2A而非5-HT1A受体，它们位于5-HT能神经元的突触后。长期而非亚急性给予选择性5-羟色胺再摄取抑制剂（SSRI）可使LC NE能神经元的自发放电活动减少。MDL 100,907可部分逆转帕罗西汀治疗大鼠中LC神经元这种被抑制的放电活动。虽然α2-肾上腺素能受体拮抗剂伊达唑胺也可增强帕罗西汀治疗大鼠中NE能神经元的放电活动，但这种增加与对照组相似。总之，长期SSRI治疗通过NE能神经元上不存在的突触后5-HT2A受体增强了5-HT对LC神经元的紧张性抑制作用。本文提出了一个推测性的神经回路来解释这些关于LC NE活动的现象。
