EFFECTS OF PRETREATMENT WITH CORTICOTROPIN-RELEASING FACTOR ON THE ELECTROPHYSIOLOGICAL RESPONSIVITY OF THE LOCUS-COERULEUS TO SUBSEQUENT CORTICOTROPIN-RELEASING FACTOR CHALLENGE
EFFECTS OF PRETREATMENT WITH CORTICOTROPIN-RELEASING FACTOR ON THE ELECTROPHYSIOLOGICAL RESPONSIVITY OF THE LOCUS-COERULEUS TO SUBSEQUENT CORTICOTROPIN-RELEASING FACTOR CHALLENGE
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DOI：
10.1016/0306-4522(95)00222-5
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发表时间：
1995-11-01
期刊：
影响因子：
3.3
通讯作者：
FOOTE, SL
中科院分区：
文献类型：
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作者：
CONTI, LH;FOOTE, SL
外源性和应激诱导的内源性促肾上腺皮质激素释放因子的急性中枢给药都会导致构成蓝斑的去甲肾上腺素能神经元的电生理激活。本实验旨在研究外源性促肾上腺皮质激素释放因子单次或多次脑室内预处理是否会改变大鼠蓝斑对随后促肾上腺皮质激素释放因子刺激的电生理反应。单一促肾上腺皮质激素释放因子（3 μ g）预处理可显著减弱24和72小时刺激诱导的蓝斑活化，但96小时后没有减弱，而单一载体预处理在任何预处理至测试间隔内对后续刺激的反应均无显著影响。用促肾上腺皮质激素释放因子或载药重复预处理，在最终预处理后24小时完全减弱蓝斑对攻毒的反应。在最后一次车辆预处理72小时后，挑战导致蓝斑座活性显著增加，尽管反应低于未处理对照组。在此（72小时）时间点，反复使用促肾上腺皮质激素释放因子预处理的大鼠，刺激继续对蓝斑活性无影响。重复预处理停止一周（168 h）后，刺激导致蓝斑座活性显著增加，与车辆预处理大鼠的对照组相同，但与促肾上腺皮质激素释放因子预处理大鼠的对照组相比有所降低。最后一次重复促肾上腺皮质激素释放因子预处理后24 h蓝斑神经元基础放电率显著低于未处理对照组。因此，在这些大鼠中，刺激未能增加神经元活动不是由于强直性放电率升高引起的“天花板”效应。重复的载体预处理产生的功能变化类似于外源性促肾上腺皮质激素释放因子的作用。一种假说认为，反复的载体预处理是应激性的，导致内源性促肾上腺皮质激素释放因子的反复释放。这一假设是通过确定蓝斑神经元是否在反复服用促肾上腺皮质激素释放因子拮抗剂后仍然对挑战有反应来检验的。因此，我们还研究了拮抗剂[D-Phe，（12）Nle, c -21,38(α) MeLeu(37)]CRF（12-41）反复预处理的效果。挑战导致最终拮抗剂预处理后24 h放电率显著增加，为该假设提供了支持。此外，在反复用载药预处理的大鼠中，乙醇刺激诱导蓝斑座活性的增加与未处理的对照组相同。这些结果表明，先前暴露于促肾上腺皮质激素释放因子，或反复轻度应激的车辆输注，降低蓝斑对促肾上腺皮质激素释放因子的反应性，并揭示这两种神经递质系统之间的关系是可以改变的。这种改变的关系可能会导致压力相关的情感障碍，其中两个系统都有牵连。
Both acute central administration of exogenous, and stress-induced release of endogenous corticotropin-releasing factor result in electrophysiological activation of the noradrenergic neurons constituting the locus coeruleus. The present experiments were designed to examine whether single (1) or repeated (8) intracerebroventricular pretreatment with exogenous corticotropin-releasing factor would alter locus coeruleus electrophysiological responsivity to subsequent corticotropin-releasing factor challenge in rats. A single corticotropin-releasing factor (3 mu g) pretreatment significantly attenuated challenge-induced locus coeruleus activation 24 and 72, but not 96 h later, while a single vehicle pretreatment had no significant effect on the response to subsequent challenge at any pretreatment-to-test interval. Repeated pretreatment with either corticotropin-releasing factor or vehicle completely attenuated locus coeruleus response to challenge 24 h after the final pretreatment. Seventy-two hours after the last vehicle pretreatment, challenge resulted in a significant increase in locus coeruleus activity, though the response was less than in naive controls. Challenge continued to produce no effect on locus coeruleus activity in repeated corticotropin-releasing factor-pretreated rats at this (72 h) time point. One week (168 h) after the cessation of repeated pretreatment, challenge resulted in a significant increase in locus coeruleus activity which was equal to that of naive controls in vehicle-pretreated rats, but reduced by comparison to controls in corticotropin-releasing factor-pretreated rats.Basal discharge rates of locus coeruleus neurons 24 h after the last repeated corticotropin-releasing factor pretreatment were significantly less than in naive controls. Thus, the failure of challenge to increase neuronal activity in these rats was not due to a ''ceiling'' effect caused by elevated tonic discharge rate.Repeated vehicle pretreatment produced a functional change similar to that produced by exogenous corticotropin-releasing factor administration. One hypothesis is that repeated vehicle pretreatment was stressful and caused the repeated release of endogenous corticotropin-releasing factor. This hypothesis was tested by determining whether locus coeruleus neurons remained responsive to challenge following repeated administration of a corticotropin-releasing factor antagonist. Thus, the effect of repeated pretreatment with the antagonist, [D-Phe,(12)Nle,C-21,38(alpha) MeLeu(37)]CRF(12-41) was also examined. Challenge resulted in a significant increase in discharge rate 24 h after the final antagonist pretreatment, providing support for the hypothesis. Additionally, in rats repeatedly pretreated with vehicle, carbachol challenge induced an increase in locus coeruleus activity equal to that induced in naive controls.These results indicate that prior exposure to corticotropin-releasing factor, or the repeated mild stress of vehicle infusions, reduces locus coeruleus responsiveness to corticotropin-releasing factor, and reveal that the relationship between these two neurotransmitter systems is modifiable. This altered relationship may contribute to stress-related affective disorders in which both systems have been implicated.