Do antidepressants affect locus coeruleus consistently?

描述（由申请人提供）：这里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的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的AID治疗都会降低LC神经元活性的可能性。最近，我们报道，在实验动物（大鼠）中，在所有AD治疗后，包括几种药物治疗和电痉挛休克（ECS）， LC神经元的自发放电率和感觉诱发的“爆发”放电都降低了。这种变化是由于慢性药物雾化（即皮下微型泵14天和30天）5种AD药物（2种三环类药物、2种SSRIs类药物和1种MAO抑制剂）和一系列5种ECSs所致。这些发现，加上之前积累的结果，形成了一个相当大的数据体，表明AD治疗降低了LC活性。

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.