Centre for Psychiatric Research, Aarhus University Hospital, Skovagervej 2, 8240 Risskov, Denmark.
Eur Neuropsychopharmacol. 2012 Oct;22(10):751-60. doi: 10.1016/j.euroneuro.2012.02.001. Epub 2012 Mar 9.
According to current theories on the etiopathogenesis and pathophysiology of depression, both GABAergic and monoaminergic transmitter systems are perturbed. Consequently, the present study addressed the putative antidepressant action of the sedative-hypnotic GABAA receptor agonist, gaboxadol, separately and in combination with the selective serotonin reuptake inhibitor (SSRI) escitalopram. The rat chronic mild stress model was used to test the chronic antidepressant properties of gaboxadol in this depression model. Sucrose intake used as a read-out on anhedonic-like behavior indicated that the drug response rate for gaboxadol (5 mg/kg/day, i.p.) was similar to that measured for escitalopram (5 mg/kg/day, i.p.), however, the rate increased when the two drugs were co-administered, suggesting a synergistic action. Using in vivo electrophysiological recordings in dorsal raphe nucleus (DRN) of anesthetised rats, the present results showed that one week treatment with gaboxadol (5 mg/kg/day, i.p.) or with escitalopram (5 mg/kg/day, i.p.), followed by a 24 h washout period, did not affect DRN 5-HT neuronal firing per se, but in rats treated with both drugs for one week, the firing rate of DRN 5-HT neurons was significantly increased. Immunohistochemical estimations of cell proliferation in the hippocampal dentate gyrus did not reveal any effect of gaboxadol on chronic mild stressed rats, indicating that neurogenesis per se is not systematically associated with recovery from anhedonic-like behavior. Taken together, our data reveal for the first time an antidepressant action of gaboxadol and indicate a synergistic mechanism, regarding rapid onset of action and efficacy, when co-administered with escitalopram.
根据目前关于抑郁症的病因和病理生理学的理论，γ-氨基丁酸能和单胺能递质系统都受到干扰。因此，本研究分别研究了镇静-催眠 GABA A 受体激动剂gaboxadol 以及选择性 5-羟色胺再摄取抑制剂（SSRI）escitalopram 联合使用时的潜在抗抑郁作用。本研究采用慢性轻度应激大鼠模型来测试 gaboxadol 在该抑郁模型中的慢性抗抑郁特性。作为快感缺失样行为的读出，蔗糖摄入量表明，gaboxadol（5mg/kg/天，ip）的药物反应率与 escitalopram（5mg/kg/天，ip）相似，但是当两种药物联合使用时，药物反应率增加，提示存在协同作用。本研究使用麻醉大鼠背侧中缝核（DRN）的体内电生理记录，结果表明，gaboxadol（5mg/kg/天，ip）或 escitalopram（5mg/kg/天，ip）治疗一周后，24 小时洗脱期内，本身并不影响 DRN 5-HT 神经元放电，但在两种药物联合治疗一周的大鼠中，DRN 5-HT 神经元的放电率显著增加。免疫组织化学测定海马齿状回的细胞增殖，没有发现 gaboxadol 对慢性轻度应激大鼠有任何影响，表明神经发生本身并不与快感缺失样行为的恢复系统相关。总之，我们的数据首次揭示了 gaboxadol 的抗抑郁作用，并表明当与 escitalopram 联合使用时，在快速起效和疗效方面存在协同作用机制。
