Effects of acute and chronic ketoconazole administration on hypothalamo--pituitary--adrenal axis activity and brain corticotropin-releasing hormone.
Effects of acute and chronic ketoconazole administration on hypothalamo--pituitary--adrenal axis activity and brain corticotropin-releasing hormone.
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急性和慢性酮康唑给药对下丘脑-垂体-肾上腺轴活动和脑促肾上腺皮质激素释放激素的影响。
DOI：
10.1016/j.psyneuen.2004.02.004
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
Goeders,NickE
中科院分区：
文献类型：
--
作者：
Smagin,GennadyN;Goeders,NickE
几年来，我们一直在研究酮康唑对大鼠可卡因奖赏的影响。然而，我们最近证实，酮康唑引起的可卡因自我管理和恢复的变化并不总是与血浆皮质酮的减少相对应，这表明其他机制必须是我们观察到的行为效应的基础。因此，本实验旨在确定急性、重复和慢性酮康唑给药对大鼠下丘脑和下丘脑外脑部位促肾上腺皮质激素释放激素（CRH）含量的影响，给药方案与我们在行为研究中使用的给药方案相同。虽然酮康唑显著增加了躯干血中ACTH的浓度，但对血浆皮质醇、皮质酮和睾酮无显著影响。酮康唑急性给药后正中隆起CRH含量也显著增加，但在重复或慢性给药后未达到统计学显著性。然而，急性，反复和慢性治疗与酮康唑每一个显着增加CRH含量在内侧前额叶皮层（MPC），但并没有一贯影响肽在任何其他大脑区域的研究。由于MPC和CRH与可卡因的神经生物学有关，因此CRH诱导的多巴胺能神经传递的改变可能在这种肽对可卡因反应性的影响中起重要作用。与以前的研究结果一起，这些数据表明，酮康唑可能会影响可卡因的奖励，至少部分，通过与MPC内的多巴胺和CRH的相互作用。
We have been investigating the effects of ketoconazole on cocaine reward in rats for several years now. However, we recently confirmed that ketoconazole-induced changes in cocaine self-administration and reinstatement do not always correspond with decreases in plasma corticosterone, which suggests that other mechanisms must be underlying the behavioral effects that we observe. This experiment was therefore designed to determine the effects of acute, repeated and chronic ketoconazole administration on corticotropin-releasing hormone (CRH) content in hypothalamic and extra-hypothalamic brain sites in rats following the same dosing regimen that we use in our behavioral studies. Although ketoconazole significantly increased the concentration of ACTH in trunk blood, there were no significant effects on plasma cortisol, corticosterone or testosterone. There was also a significant increase in CRH content in the median eminence after the acute administration of ketoconazole that just failed to reach statistical significance following repeated or chronic administration. However, acute, repeated and chronic treatment with ketoconazole each significantly increased CRH content in the medial prefrontal cortex (MPC), but did not consistently affect the peptide in any other brain region studied. Since the MPC and CRH have been implicated in the neurobiology of cocaine, CRH-induced alterations in dopaminergic neurotransmission may play an important role in this peptide’s effects on cocaine responsiveness. Taken together with the results from previous studies, these data suggest that ketoconazole may affect cocaine reward, at least in part, through interactions with dopamine and CRH within the MPC.