Do antidepressants affect locus coeruleus consistently?

抗抑郁药是否持续影响蓝斑？

• 批准号: 6685857
• 负责人: JAY MICHAEL WEISS
• 金额: $ 19万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6685857
• 关键词: Do; antidepressants; affect; locus; coeruleus

DESCRIPTION (provided by applicant): The research proposed here will assess how electrophysiological activity of neurons of the major noradrenergic cell-body group of the brain, the locus coeruleus (LC), is altered by effective antidepressant (AD) treatment. The primary impetus for this research is evidence from both preclinical and clinical research that raises the possibility that all presently-known effective AID treatments reduce activity of LC neurons. Recently, we reported that, in experimental animals (rats), both spontaneous firing rate and sensory-evoked "burst" firing of LC neurons were decreased following all AD treatments examined, including several types of drug therapy and also electroeonvulsive shock (ECS). This change resulted from chronic drug admires" tration (i.e., for 14 and 30 days by subcutaneous minipump) of five AD drugs (two tricyclics, two SSRIs, and an MAO inhibitor) and a series of 5 ECSs. These findings, together with previously accumulated results, form a sizable body of data indicating that AD treatments decrease LC activity. The present study will continue to measure both spontaneous and sensory-evoked LC electrophysiological activity, extending the number of AD treatments surveyed and addressing important remaining issues. First, effects produced by chronic administration of several AD and non-AD drugs that we have not examined previously as well as by promising new therapies (i.e., a CRH antagonist, NK-1 receptor blocker, and rTMS) will be determined. Particular attention is directed to two AD drugs (mianserin and mirtazapine) that block a2pha adrenergic receptors and thus acutely increase (rather than decrease) LC activity; however, data from chronic administration of these drugs are contradictory. By the conclusion of this experiment, our fmdmgs plus those of others will have determined effects on LC activity of a relatively comprehensive list of known effective AD treatments and also will have begun to assess whether reduced LC activity is specific to ADs (by testing non-AD drugs). Second, because mount of drug (i.e. blood level of drug) may be quite important in determining response, changes in LC activity resulting from different doses of desipramme (a tricyclic), sertraline (an SSRI), and the two drugs that block a2 receptors (mirtazapine and mianserin) will be assessed, with blood levels also measured. Finally, effects on LC activity will be determined for these four drugs when the rats take drug orally in a manner analogous to taking a pill. While minipumps provide reliable and consistent drug delivery for the rat, humans usually take drug in pill form, which introduces drug orally in a bolus. Effects might differ if drug is given in this way and blood levels vary somewhat across the day. Consequently, a method has been developed to induce rats to voluntarily take drug orally in a manner similar to a pill, and effects of this will be assessed.

描述（由申请人提供）：本文提出的研究将评估有效的抗抑郁药（AD）治疗如何改变大脑主要去甲肾上腺素能细胞体群蓝斑（LC）神经元的电生理活动。这项研究的主要推动力是来自临床前和临床研究的证据，这些证据提出了目前已知的所有有效 AID 治疗都会降低 LC 神经元活性的可能性。最近，我们报道说，在实验动物（大鼠）中，在接受所有 AD 治疗（包括几种药物治疗和电惊厥（ECS））后，LC 神经元的自发放电率和感觉诱发的“爆发”放电均下降。这种变化是由五种 AD 药物（两种三环类药物、两种 SSRI 和一种 MAO 抑制剂）和一系列 5 种 ECS 的长期药物治疗（即通过皮下微型泵持续 14 和 30 天）引起的。这些发现与之前的结果一起累积的结果形成了大量数据，表明 AD 治疗会降低 LC 活性。 本研究将继续测量自发性和感觉诱发的 LC 电生理活动，扩大所调查的 AD 治疗数量并解决重要的遗留问题。首先，我们将确定长期服用几种我们以前没有研究过的 AD 和非 AD 药物以及有前途的新疗法（即 CRH 拮抗剂、NK-1 受体阻滞剂和 rTMS）所产生的效果。特别关注两种 AD 药物（米安舍林和米氮平），它们阻断 a2pha 肾上腺素能受体，从而急剧增加（而不是减少）LC 活性；然而，长期服用这些药物的数据是矛盾的。 通过本实验的结论，我们的 fmdmg 以及其他药物将对相对全面的已知有效 AD 治疗列表的 LC 活性产生确定的影响，并且还将开始评估降低的 LC 活性是否特定于 AD（通过测试非AD药物）。其次，由于药物量（即药物的血液浓度）对于确定反应可能非常重要，因此不同剂量的地昔普兰（三环类药物）、舍曲林（SSRI）以及两种阻断 a2 受体的药物会导致 LC 活性的变化（米氮平和米安色林）将进行评估，并测量血液水平。最后，当大鼠以类似于服用药丸的方式口服药物时，将确定这四种药物对 LC 活性的影响。虽然微型泵为大鼠提供可靠且一致的药物输送，但人类通常以丸剂形式服用药物，即以丸剂形式口服药物。如果以这种方式给药，效果可能会有所不同，而且一天中的血液浓度会有所不同。因此，开发了一种方法来诱导大鼠以类似于药丸的方式自愿口服药物，并将评估其效果。