Paroxetine-induced increase in activity of locus coeruleus neurons in adolescent rats: implication of a countertherapeutic effect of an antidepressant.
Paroxetine-induced increase in activity of locus coeruleus neurons in adolescent rats: implication of a countertherapeutic effect of an antidepressant.
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DOI：
10.1038/npp.2010.34
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发表时间：
2010-07
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影响因子：
--
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中科院分区：
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抗抑郁药（AD）药物，尤其是选择性血清素再摄取抑制剂和帕罗西汀（PAR），在青少年患者（儿童和青少年）的早期治疗中会增加自杀率，这给临床医生治疗抑郁症带来了两难境地。虽然临床前研究不能解决这一领域的争议，但我们目前的研究结果可能为AD药物在某些情况下如何加剧而不是改善抑郁状态提供了见解。临床和临床前证据表明，大脑中主要的去肾上腺素能细胞群蓝斑（LC）在抑郁症患者中过度活跃，相反，有效的阿尔茨海默病治疗会降低LC神经元的活性。我们在此报告，短期（2天和4天）给药PAR会增加年轻大鼠LC神经元的活动（自发放电率和感觉诱发反应），与通常在成年大鼠中观察到的“治疗性”活动减少相反。幼龄大鼠的PAR血液水平低于成年大鼠，尽管成年大鼠低剂量PAR产生的类似低血液水平未能使LC活性增加。此外，在游泳测试中测定了年轻大鼠的活动，以评估抑郁样反应。相同剂量/持续时间的PAR使年轻大鼠LC活性增加最多，但却使游泳试验活性降低，这表明在年轻大鼠中短暂给予PAR可以促进而不是减轻抑郁状态。这些结果提供了一个模型，可以帮助筛选潜在的辅助治疗，以避免ad的早期不良反应。
Concern that antidepressant (AD) drugs, especially selective serotonin reuptake inhibitors and paroxetine (PAR) in particular, can increase suicidality during the early treatment of juvenile patients (children and adolescents) has created a dilemma for clinicians treating depressives. Though preclinical research cannot resolve controversy in this area, our present findings may provide insight into how AD drugs might, under certain conditions, exacerbate rather than ameliorate the depressive state. Both clinical and preclinical evidence indicates that the principle noradrenergic cell group in the brain, the locus coeruleus (LC), is over-active in depressives and that, conversely, effective AD treatments decrease activity of LC neurons. We report here that short-term (2 and 4 day) administration of PAR produces an increase in the activity of LC neurons (spontaneous firing rate and sensory-evoked responses) in young rats, contrary to the “therapeutic” decrease in activity typically observed in adult rats. Blood levels of PAR were lower in young rats than in adult rats, though similar low blood levels produced by a lower dose of PAR in adult rats failed to produce an increase in LC activity. Additionally, activity of young rats in the swim test was determined to assess depressive-like responses. The same dose/durations of PAR which produced the largest increases in LC activity in young rats produced decreases in swim-test activity, indicating that brief administration of PAR in young rats can promote, rather than reduce, the depressive state. These results offer a model which may help screen potential adjunctive treatments to avoid early adverse effects of ADs.
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影响因子：
1.9
作者：
Mosholder, AD;Willy, M
通讯作者：
Willy, M
影响因子：
--
作者：
Hammad, TA;Laughren, T;Racoosin, J
通讯作者：
Racoosin, J
影响因子：
5
作者：
KORF, J;BUNNEY, BS;AGHAJANIAN, GK
通讯作者：
AGHAJANIAN, GK
影响因子：
6.7
作者：
LUNDMARK, J;THOMSEN, IS;WALINDER, J
通讯作者：
WALINDER, J
DOI：
10.1073/pnas.87.19.7522
发表时间：
1990-10-01
影响因子：
11.1
作者：
NESTLER, EJ;MCMAHON, A;DUMAN, RS
通讯作者：
DUMAN, RS