O'Leary Olivia F, Bechtholt Anita J, Crowley James J, Valentino Rita J, Lucki Irwin
Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Eur Neuropsychopharmacol. 2007 Feb;17(3):215-26. doi: 10.1016/j.euroneuro.2006.06.012. Epub 2006 Sep 25.
Serotonin neurons of the dorsal raphe nucleus (DRN) receive dense noradrenergic innervation and are under tonic activation by noradrenergic input. Thus, afferent noradrenergic input to the DRN could modify the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) by regulating serotonergic transmission. This study investigated whether noradrenergic innervation of the DRN contributes to the acute behavioral effects of different types of antidepressant drugs in the mouse tail suspension test (TST). Noradrenergic terminals in the DRN were destroyed selectively by the local application of 6-hydroxydopamine (6-OHDA). Immunohistochemical analysis confirmed the presence of noradrenergic fibers in the mouse DRN, that 6-OHDA-induced destruction of noradrenergic terminals was confined to the DRN, and serotonergic cell bodies were not affected by 6-OHDA treatment. The antidepressants tested included the SSRIs, fluoxetine and citalopram, and the norepinephrine reuptake inhibitor (NRI) desipramine. The behavioral effects of fluoxetine (20 mg/kg, IP) were blocked by the destruction of noradrenergic terminals. In contrast, pretreatment with 6-OHDA did not alter the ability of citalopram (20 mg/kg, IP) or desipramine (10 mg/kg, IP) to reduce immobility in the TST. Destruction of noradrenergic projections from the locus ceruleus (LC) by DSP-4 treatment did not alter the behavioral effects of any of the antidepressants tested, or the presence of noradrenergic terminals in the DRN, thus indicating that noradrenergic pathways originating from the LC do not mediate the acute behavioral effects of antidepressants in this test. Thus, afferent noradrenergic activity at the level of the DRN can modulate serotonergic transmission in forebrain structures and the behavioral effects of SSRIs, such as fluoxetine, which use noradrenergic input to the DRN to increase forebrain serotonin.
中缝背核（DRN）的5-羟色胺能神经元接受密集的去甲肾上腺素能神经支配，并受到去甲肾上腺素能输入的紧张性激活。因此，传入DRN的去甲肾上腺素能输入可通过调节5-羟色胺能传递来改变选择性5-羟色胺再摄取抑制剂（SSRI）的抗抑郁作用。本研究调查了DRN的去甲肾上腺素能神经支配是否有助于不同类型抗抑郁药物在小鼠悬尾试验（TST）中的急性行为效应。通过局部应用6-羟基多巴胺（6-OHDA）选择性地破坏DRN中的去甲肾上腺素能终末。免疫组织化学分析证实小鼠DRN中存在去甲肾上腺素能纤维，6-OHDA诱导的去甲肾上腺素能终末破坏局限于DRN，且5-羟色胺能细胞体不受6-OHDA处理的影响。所测试的抗抑郁药物包括SSRI氟西汀和西酞普兰，以及去甲肾上腺素再摄取抑制剂（NRI）地昔帕明。去甲肾上腺素能终末的破坏阻断了氟西汀（20mg/kg，腹腔注射）的行为效应。相反，用6-OHDA预处理并未改变西酞普兰（20mg/kg，腹腔注射）或地昔帕明（10mg/kg，腹腔注射）减少TST中不动时间的能力。用DSP-4处理破坏蓝斑（LC）的去甲肾上腺素能投射并未改变所测试的任何一种抗抑郁药物的行为效应，也未改变DRN中去甲肾上腺素能终末的存在，因此表明源自LC的去甲肾上腺素能通路在该试验中不介导抗抑郁药物的急性行为效应。因此，DRN水平的传入去甲肾上腺素能活动可调节前脑结构中的5-羟色胺能传递以及SSRI（如氟西汀）的行为效应，氟西汀利用传入DRN的去甲肾上腺素能输入来增加前脑5-羟色胺水平。
