Romero L, Bel N, Artigas F, de Montigny C, Blier P
Department of Neurochemistry, CID, Consejo Superior de Investigaciones Cientificas (CSIC), Barcelona, Spain.
Neuropsychopharmacology. 1996 Oct;15(4):349-60. doi: 10.1016/0893-133X(95)00240-E.
In microdialysis studies, somatodendritic 5-HT1A receptors in the dorsal raphe nucleus (DRN) were activated by the local infusion of 50 microM citalopram, a selective 5-HT reuptake inhibitor (SSRI). This reduced extracellular 5-HT by about 50% in dorsal striatum, an area receiving 5-HT afferents exclusively from the DRN. (-)Pindolol dose-dependently attenuated this citalopram-induced reduction of striatal extracellular 5-HT. Consistent with its 5-HT reuptake blocking properties, single doses of the SSRI paroxetine (1 and 3 mg/kg IP) and citalopram (1 mg/kg IP) significantly elevated extracellular 5-HT in the dorsal striatum. Pretreatment with (-)pindolol (15 mg/kg IP) potentiated the effect of 3 mg/kg paroxetine and 1 mg/kg citalopram on striatal extracellular 5-HT. A 2-day treatment with 10 mg/kg/day (SC) of paroxetine reduced by 60% the spontaneous activity of 5-HT neurons of the DRN. However, 5-HT neurons displayed normal activity in rats treated with paroxetine and (-)pindolol for 2 days. The inhibitory effect of LSD on 5-HT neuronal firing activity was also markedly attenuated in (-)pindolol-treated rats, indicating that somatodendritic 5-HT1A receptors were blocked by (-)pindolol. To determine whether (-)pindolol also blocked postsynaptic 5-HT1A receptors in hippocampus, 5-HT and the prototypical 5-HT1A agonist 8-OH-DPAT were applied by microiontophoresis onto CA3 pyramidal neurons following the same treatment. (-)Pindolol did not modify the responsiveness of these neurons to 5-HT and 8-OH-DPAT. Taken together, these results indicate that (-)pindolol can potentiate the effects of an SSRI on extracellular 5-HT concentration by preventing the activation of somatodendritic 5-HT1A autoreceptors resulting from the blockade of the 5-HT transporter in the raphe. This presumably leads to enhanced 5-HT neurotransmission because (-)pindolol would not alter the responsiveness of certain postsynaptic 5-HT1A receptors, such as those located on hippocampal CA3 pyramidal neurons. These results provide a neurobiological basis for the reported potentiation of certain antidepressant drugs by pindolol in major depression.
在微透析研究中，通过局部注入50微摩尔/升的西酞普兰（一种选择性5-羟色胺再摄取抑制剂，SSRI）激活中缝背核（DRN）中的树突体5-羟色胺1A受体。这使背侧纹状体（该区域仅从中缝背核接收5-羟色胺传入神经）中的细胞外5-羟色胺减少了约50%。（-）吲哚洛尔剂量依赖性地减弱了西酞普兰诱导的纹状体细胞外5-羟色胺的减少。与其5-羟色胺再摄取阻断特性一致，单剂量的SSRI帕罗西汀（1和3毫克/千克腹腔注射）和西酞普兰（1毫克/千克腹腔注射）显著提高了背侧纹状体中的细胞外5-羟色胺。用（-）吲哚洛尔（15毫克/千克腹腔注射）预处理可增强3毫克/千克帕罗西汀和1毫克/千克西酞普兰对纹状体细胞外5-羟色胺的作用。用10毫克/千克/天（皮下注射）的帕罗西汀进行为期2天的治疗，可使中缝背核5-羟色胺神经元的自发活动减少60%。然而，在用帕罗西汀和（-）吲哚洛尔治疗2天的大鼠中，5-羟色胺神经元表现出正常活动。在（-）吲哚洛尔治疗的大鼠中，麦角酸二乙胺对5-羟色胺神经元放电活动的抑制作用也明显减弱，表明树突体5-羟色胺1A受体被（-）吲哚洛尔阻断。为了确定（-）吲哚洛尔是否也阻断海马中的突触后5-羟色胺1A受体，在相同处理后，通过微离子透入法将5-羟色胺和典型的5-羟色胺1A激动剂8-羟基二丙胺基四氢萘施加到CA3锥体神经元上。（-）吲哚洛尔并未改变这些神经元对5-羟色胺和8-羟基二丙胺基四氢萘的反应性。综上所述，这些结果表明，（-）吲哚洛尔可通过防止中缝中5-羟色胺转运体被阻断而导致的树突体5-羟色胺1A自身受体激活，来增强SSRI对细胞外5-羟色胺浓度的作用。这可能会导致5-羟色胺神经传递增强，因为（-）吲哚洛尔不会改变某些突触后5-羟色胺1A受体的反应性，例如位于海马CA3锥体神经元上的那些受体。这些结果为吲哚洛尔在重度抑郁症中增强某些抗抑郁药物作用的报道提供了神经生物学基础。
