Do antidepressants affect locus coeruleus consistently?

描述(申请人提供)：这项研究将评估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如何通过有效的抗抑郁药物(AD)治疗而改变。这项研究的主要推动力是来自临床前和临床研究的证据，这些证据提高了目前已知的所有有效的AID治疗降低LC神经元活动的可能性。最近，我们报道了在实验动物(大鼠)中，在包括几种药物治疗和电诱导性休克(ECS)在内的所有AD治疗后，LC神经元的自发放电和感觉诱发的“爆发性”放电都降低了。这一变化是由5种AD药物(2种三环类药物、2种SSRI药物和1种MAO抑制剂)和5种ECS的慢性用药(即皮下注射14天和30天)和一系列ECS造成的。这些发现与先前积累的结果一起形成了大量数据，表明AD治疗会降低LC活性。 本研究将继续测量自发和感觉诱发的LC电生理活动，扩大AD治疗的数量，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检查过的AD和非AD药物以及有希望的新疗法(即CRH拮抗剂、NK-1受体阻滞剂和rTMS)所产生的效果。特别要注意的是两种AD药物(米安色林和米氮平)，它们阻断α-肾上腺素能受体，从而显著增加(而不是降低)LC活性；然而，来自长期服用这些药物的数据是相互矛盾的。到本实验结束时，我们的fmdmgs加上其他人的fmdmgs将确定相对全面的已知有效AD治疗方法对LC活性的影响，并将开始评估LC活性降低是否是ADS特有的(通过测试非AD药物)。其次，由于药物的量(即药物的血药水平)在确定反应时可能相当重要，因此将评估不同剂量的地昔普拉米(三环类药物)、舍曲林(一种SSRI)以及两种阻断a2受体的药物(米氮平和米安色林)引起的LC活性变化，并测量血液水平。最后，当大鼠以类似于服药的方式口服药物时，将确定这四种药物对LC活性的影响。虽然小型泵为大鼠提供了可靠和一致的药物输送，但人类通常以药丸的形式服用药物，即一剂一剂地口服药物。如果以这种方式给药，并且血液水平在一天中略有不同，效果可能会有所不同。因此，已经开发出一种方法来诱导大鼠以类似于药片的方式自愿口服药物，并将评估其效果。

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.