Boyer P A, Skolnick P, Fossom L H
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD, USA.
J Mol Neurosci. 1998 Jun;10(3):219-33. doi: 10.1007/BF02761776.
Chronic administration of antidepressants produces region-specific adaptive changes in the radioligand binding properties of N-methyl-D-aspartate (NMDA) receptors. We hypothesized that this effect of chronic antidepressant administration was owing to an alteration in NMDA receptor subunit composition. This hypothesis was examined using in situ hybridization with [35S]-labeled riboprobes to quantify the impact of chronic (16 d) injection with either imipramine (15 mg/kg) or citalopram (20 mg/kg) on the levels of transcripts encoding NMDA receptor subunits in mouse brain. These antidepressants altered the levels of mRNA encoding the zeta-subunit in a parallel fashion, with both drugs either reducing transcript levels (e.g., in the cortex, cerebellum, thalamus, and striatum) or producing no substantial effects (e.g., hippocampus). In contrast, these antidepressants often produced distinct, region-specific effects on mRNA levels encoding the epsilon family of subunits. For example, citalopram treatment produced widespread reductions in epsilon 1-subunit mRNA levels (e.g., in frontal cortex, CA2 of hippocampus, and amygdala), whereas imipramine reduced levels of this transcript only in the amygdala. Conversely, imipramine treatment produced widespread reductions in epsilon 2-subunit mRNA levels (e.g., in cortex, CA1-4 of hippocampus, and amygdala), whereas the effects of citalopram on levels of this transcript were largely restricted to amygdala. These findings indicate that long-term antidepressant treatment produces region-specific changes in expression of transcripts for NMDA receptor subunits, presumably altering NMDA receptor composition. Because subunit composition determines the physiological and pharmacological properties of NMDA receptors, these changes may play a critical role in the therapeutic actions of structurally diverse antidepressants.
长期服用抗抑郁药会使N-甲基-D-天冬氨酸（NMDA）受体的放射性配体结合特性产生区域特异性适应性变化。我们推测，长期服用抗抑郁药的这种作用是由于NMDA受体亚基组成的改变。使用[35S]标记的核糖探针进行原位杂交，以量化长期（16天）注射丙咪嗪（15毫克/千克）或西酞普兰（20毫克/千克）对小鼠脑中编码NMDA受体亚基的转录本水平的影响，从而检验这一假设。这些抗抑郁药以平行方式改变了编码ζ亚基的mRNA水平，两种药物均降低了转录本水平（如在皮质、小脑、丘脑和纹状体中），或未产生实质性影响（如在海马体中）。相比之下，这些抗抑郁药对编码ε亚基家族的mRNA水平常常产生不同的、区域特异性的影响。例如，西酞普兰治疗使ε1亚基mRNA水平普遍降低（如在额叶皮质、海马体CA2区和杏仁核中），而丙咪嗪仅在杏仁核中降低了该转录本的水平。相反，丙咪嗪治疗使ε2亚基mRNA水平普遍降低（如在皮质、海马体CA1-4区和杏仁核中），而西酞普兰对该转录本水平的影响主要局限于杏仁核。这些发现表明，长期抗抑郁治疗会使NMDA受体亚基转录本的表达产生区域特异性变化，推测会改变NMDA受体的组成。由于亚基组成决定了NMDA受体的生理和药理特性，这些变化可能在结构多样的抗抑郁药的治疗作用中起关键作用。
