Cell Biology and Anatomy, Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Eur J Neurosci. 2011 Jul;34(2):221-34. doi: 10.1111/j.1460-9568.2011.07757.x. Epub 2011 Jul 4.
Depression is a debilitating mental disorder, and selective serotonin reuptake inhibitors (SSRIs) constitute the first-line antidepressant treatment choice for the clinical management of this illness; however, the mechanisms underlying their therapeutic actions and side effects remain poorly understood. Here, we compared the effects of two SSRIs, fluoxetine and citalopram, on synaptic connectivity and the efficacy of cholinergic synaptic transmission between identified presynaptic and postsynaptic neurons from the mollusc Lymnaea. The in vitro paired cells were exposed to clinically relevant concentrations of the two SSRIs under chronic and acute experimental conditions, and the incidence of synapse formation and the efficacy of synaptic transmission were tested electrophysiologically and with fluorescent Ca(2+) imaging. We demonstrate that chronic exposure to fluoxetine, but not to citalopram, inhibits synapse formation and reduces synaptic strength, and that these effects are reversible following prolonged drug washout. At the structural level, we demonstrate that fluoxetine, but not citalopram, prevents the expression and localization of the presynaptic protein synaptophysin. Acute exposure to fluoxetine substantially reduced synaptic transmission and synaptic plasticity (post-tetanic potentiation) in established synapses, whereas citalopram reduced synaptic transmission, but not short-term synaptic plasticity. We further demonstrate that fluoxetine, but not citalopram, directly inhibits voltage-gated Ca(2+) currents in the presynaptic neuron, as well as postsynaptic responsiveness to exogenously applied neurotransmitter. This study provides the first direct evidence that fluoxetine and citalopram exert characteristic, non-specific side effects that are unrelated to their function as SSRIs, and that fluoxetine is more detrimental to synaptic physiology and structure than citalopram.
抑郁症是一种使人虚弱的精神障碍，选择性 5-羟色胺再摄取抑制剂（SSRIs）构成了这种疾病临床管理中治疗选择的一线药物；然而，它们的治疗作用和副作用的机制仍知之甚少。在这里，我们比较了两种 SSRIs，氟西汀和西酞普兰，对鉴定的来自软体动物石鳖的突触前和突触后神经元之间的突触连接和胆碱能突触传递的功效的影响。在慢性和急性实验条件下，将体外配对细胞暴露于两种 SSRIs 的临床相关浓度下，并用电生理学和荧光 Ca2+成像测试突触形成的发生率和突触传递的功效。我们证明，慢性暴露于氟西汀，但不是西酞普兰，抑制突触形成并降低突触强度，并且这些作用在长时间药物冲洗后是可逆的。在结构水平上，我们证明，氟西汀，而不是西酞普兰，防止了突触前蛋白突触小体素的表达和定位。急性暴露于氟西汀会大大降低已建立的突触中的突触传递和突触可塑性（后强直增强），而西酞普兰会降低突触传递，但不会降低短期突触可塑性。我们进一步证明，氟西汀，而不是西酞普兰，直接抑制突触前神经元中的电压门控 Ca2+电流，以及对突触后神经元对外源神经递质的反应。这项研究首次提供了直接证据，证明氟西汀和西酞普兰具有特征性的、非特异性的副作用，与它们作为 SSRIs 的功能无关，并且氟西汀比西酞普兰对突触生理学和结构的危害更大。
