Delayed Antidepressant Efficacy and the Desensitization Hypothesis.,ACS Chemical Neuroscience

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Delayed Antidepressant Efficacy and the Desensitization Hypothesis.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2019-03-11 , DOI: 10.1021/acschemneuro.8b00698
Kathryn G Commons _{1,

2} , Sofia E Linnros _{1,

2}

Affiliation

Many conventional antidepressants can quickly raise the levels of extracellular serotonin, yet their positive effects on mood ensues only weeks later. This delay in efficacy is a clinical problem that has proven difficult to overcome. Early investigation noted that the initial increases in extracellular serotonin engaged strong feedback inhibition of serotonin neurons via 5-HT1A autoreceptors, resulting in a profound reduction in their firing rate. Over the course of chronic treatment, however, firing rate returned to normal and the inhibition via 5-HT1A receptor agonists was attenuated. The coincident timeline of these phenomena led to the influential hypothesis that the relationship was causal and that gradual loss of feedback inhibition mediated by 5-HT1A receptors was critical to the delayed therapeutic onset. Simple and appealing, the desensitization hypothesis has taken strong hold, yet much of the supporting evidence is circumstantial and there are several observations that would refute a causal relationship. In particular, even though 5-HT1A receptors may desensitize, there is evidence that feedback inhibition mediated by remaining receptors persists. That is, baseline serotonin firing rate returns to normal not because of 5-HT1A desensitization but rather despite ongoing feedback inhibition. Thus, while 5-HT1A receptors remain important for emotional behavior, it may be other slow-adaptive changes triggered by antidepressants that allow for therapeutic effects, such as those involving glutamatergic synaptic plasticity.

中文翻译：

延缓抗抑郁功效和脱敏假设。

许多传统的抗抑郁药可以迅速提高细胞外血清素的水平，但仅在数周后才对情绪产生积极影响。功效的这种延迟是已经证明难以克服的临床问题。早期研究指出，细胞外5-羟色胺的最初增加是通过5-HT1A自体受体强烈地抑制5-羟色胺神经元的反馈，从而导致其放电速度大大降低。然而，在长期治疗过程中，射击频率恢复正常，并且通过5-HT1A受体激动剂的抑制作用减弱。这些现象的时间相吻合，产生了一种有影响力的假设，即这种关系是因果关系的，并且由5-HT1A受体介导的反馈抑制作用的逐渐丧失对延迟治疗起关键作用。简单而吸引人，脱敏假说已得到广泛应用，但是许多支持证据是间接的，并且有几项观察结果可以驳斥因果关系。特别是，即使5-HT1A受体可能脱敏，也有证据表明，其余受体介导的反馈抑制作用仍然存在。也就是说，血清5-羟色胺的基线放电速率恢复正常不是因为5-HT1A脱敏，而是尽管存在持续的反馈抑制作用。因此，尽管5-HT1A受体对于情绪行为仍然很重要，但可能是由抗抑郁药触发的其他缓慢适应性变化，从而产生了治疗效果，例如涉及谷氨酸能突触可塑性的那些。然而，许多支持证据是间接的，并且有一些观察结果可以反驳因果关系。特别是，即使5-HT1A受体可能脱敏，也有证据表明，其余受体介导的反馈抑制作用仍然存在。也就是说，血清5-羟色胺的基线放电速率恢复正常不是因为5-HT1A脱敏，而是尽管存在持续的反馈抑制作用。因此，尽管5-HT1A受体对于情绪行为仍然很重要，但可能是由抗抑郁药触发的其他缓慢适应性变化，从而产生了治疗效果，例如涉及谷氨酸能突触可塑性的那些。然而，许多支持证据是间接的，并且有一些观察结果可以反驳因果关系。特别是，即使5-HT1A受体可能脱敏，也有证据表明，其余受体介导的反馈抑制作用仍然存在。也就是说，血清5-羟色胺的基线放电速率恢复正常不是因为5-HT1A脱敏，而是尽管存在持续的反馈抑制作用。因此，尽管5-HT1A受体对于情绪行为仍然很重要，但可能是由抗抑郁药触发的其他缓慢适应性变化，从而产生了治疗效果，例如涉及谷氨酸能突触可塑性的那些。血清5-羟色胺的基线放电率恢复正常不是因为5-HT1A脱敏，而是尽管持续存在反馈抑制作用。因此，尽管5-HT1A受体对于情绪行为仍然很重要，但可能是由抗抑郁药触发的其他缓慢适应性变化，从而产生了治疗效果，例如涉及谷氨酸能突触可塑性的那些。血清5-羟色胺的基线放电率恢复正常不是因为5-HT1A脱敏，而是尽管持续存在反馈抑制作用。因此，尽管5-HT1A受体对于情绪行为仍然很重要，但可能是由抗抑郁药触发的其他缓慢适应性变化，从而产生了治疗效果，例如涉及谷氨酸能突触可塑性的那些。

更新日期：2019-02-26

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