Potter W Z
Section on Clinical Pharmacology, National Institute of Mental Health, Bethesda, Md. 20892, USA.
J Clin Psychiatry. 1996;57 Suppl 4:4-8.
Hypotheses of antidepressant action which argue that even norepinephrine (NE) uptake inhibitors ultimately work through potentiation of serotonergic function are critically reviewed. Preclinical electrophysiologic data can be interpreted as evidence for enhanced serotonin (5-HT) throughput as a common mechanism of action of all antidepressants. Biochemical data in rats (e.g., microdialysis) and humans (e.g., opposite effects of ECT on 5-HIAA in cerebrospinal fluid), however, suggest that more is involved than simply enhanced 5-HT function when NE uptake inhibition is combined with 5-HT uptake inhibition. The case, however, for noradrenergic effects on 5-HT function is quite strong either with regard to stimulation of alpha 1 receptors on 5-HT cell bodies or alpha 2 heteroreceptors on 5-HT nerve endings. Even the reported ability of pindolol to potentiate the antidepressant effects of 5-HT uptake inhibitors may prove to involve noradrenergic effects and not simply antagonism of 5-HT1A receptors as currently hypothesized. The biochemically specific drugs needed to directly test these concepts are not yet available. On the other hand, compounds which combine noradrenergic and serotonergic effects (e.g., alpha 2 antagonism and 5-HT2 antagonism) that go beyond those of the classic uptake inhibitors are emerging as agents to test the clinical potential of selective manipulation of these interacting neurotransmitter systems.
对认为即使去甲肾上腺素（NE）摄取抑制剂最终也是通过增强血清素能功能起作用的抗抑郁作用假说进行了批判性综述。临床前电生理数据可被解释为所有抗抑郁药共同作用机制是血清素（5-HT）通量增强的证据。然而，大鼠（如微透析）和人类（如ECT对脑脊液中5-HIAA的相反作用）的生化数据表明，当NE摄取抑制与5-HT摄取抑制相结合时，涉及的不仅仅是简单的5-HT功能增强。然而，无论是对5-HT细胞体上的α1受体还是5-HT神经末梢上的α2异受体的刺激，去甲肾上腺素能对5-HT功能的影响证据都相当充分。甚至报道的吲哚洛尔增强5-HT摄取抑制剂抗抑郁作用的能力，可能也被证明涉及去甲肾上腺素能作用，而不仅仅是如目前所假设的对5-HT1A受体的拮抗作用。目前还没有直接测试这些概念所需的生化特异性药物。另一方面，结合去甲肾上腺素能和血清素能作用（如α2拮抗和5-HT2拮抗）且超越经典摄取抑制剂作用的化合物，正作为测试选择性操纵这些相互作用神经递质系统临床潜力的药物而出现。
