STRAIN-SELECTIVE EFFECTS OF CORTICOSTERONE ON LOCOMOTOR SENSITIZATION TO COCAINE AND ON LEVELS OF TYROSINE-HYDROXYLASE AND GLUCOCORTICOID RECEPTOR IN THE VENTRAL TEGMENTAL AREA
STRAIN-SELECTIVE EFFECTS OF CORTICOSTERONE ON LOCOMOTOR SENSITIZATION TO COCAINE AND ON LEVELS OF TYROSINE-HYDROXYLASE AND GLUCOCORTICOID RECEPTOR IN THE VENTRAL TEGMENTAL AREA
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DOI：
10.1016/0306-4522(95)00018-e
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发表时间：
1995-07-01
期刊：
影响因子：
3.3
通讯作者：
NESTLER, EJ
中科院分区：
文献类型：
--
作者：
ORTIZ, J;DECAPRIO, JL;NESTLER, EJ
我们研究了两种近交大鼠（Fischer 344 和 Lewis）长期给予皮质酮的生化和行为影响，已知这两种大鼠的下丘脑-垂体-肾上腺轴和对滥用药物的行为反应不同。首先，我们通过反向磷酸化、二维凝胶电泳和蛋白质印迹分析，研究了假手术和皮质酮处理的 Fischer 和 Lewis 大鼠腹侧被盖区磷蛋白的皮质酮调节。皮质酮仅在 Fischer 大鼠的腹侧被盖区上调酪氨酸羟化酶免疫反应性并降低胶质原纤维酸性蛋白磷酸化状态，而在 Lewis 大鼠中未见变化。我们还研究了皮质酮对可卡因运动敏感性的影响，这种行为已知受腹侧被盖区调节。在 Fischer 大鼠中，慢性皮质酮预处理导致可卡因致敏的发生，而在假预处理的 Fischer 大鼠中则不存在这种情况。相比之下，Lewis 大鼠无论有或没有皮质酮预处理都会产生可卡因过敏。因此，在 Fischer 大鼠中观察到的皮质酮对生化和行为的影响在 Lewis 大鼠中不存在。接下来，我们研究了某些转录因子（被认为在酪氨酸羟化酶表达中发挥作用）可能参与皮质酮的这些菌株选择性作用的可能性。皮质酮治疗降低了Lewis大鼠腹侧被盖区的糖皮质激素受体免疫反应水平，但对Fischer大鼠没有影响。此外，与Lewis大鼠相比，未接受药物治疗的Fischer大鼠腹侧被盖区环AMP反应元件结合蛋白的免疫反应性水平更高，而在这两种品系中均未观察到皮质酮的影响。这些发现表明，下丘脑-垂体-肾上腺轴对滥用药物反应的调节是在Fischer大鼠中观察到的遗传决定特征，但在Lewis大鼠中不存在。我们提出，皮质酮给药下调Lewis大鼠腹侧被盖区的糖皮质激素受体，从而阻止对皮质酮治疗的其他适应，而在Fischer大鼠腹侧被盖区，糖皮质激素受体下调的缺乏和环AMP反应元件结合蛋白的高基础水平可能促进糖皮质激素的转录、生化和行为作用。
We have studied biochemical and behavioral effects of chronic corticosterone administration in two inbred rat stains (Fischer 344 and Lewis), known to differ in their hypothalamic-pituitary-adrenal axis and in their behavioral responses to drugs of abuse. First, we studied corticosterone regulation of phosphoproteins in the ventral tegmental area of sham- and corticosterone-treated Fischer and Lewis rats, by means of back-phosphorylation and two-dimensional gel electrophoresis and Western blotting analysis. Corticosterone administration upregulated tyrosine hydroxylase immunoreactivity and decreased glial-fibrillary acidic protein phosphorylation state in the ventral tegmental area of Fischer rats only, with no changes seen in Lewis rats. We also studied corticosterone effects on locomotor sensitization to cocaine, a behavior known to be regulated by the ventral tegmental area. In Fischer rats, chronic corticosterone pretreatment resulted in development of cocaine sensitization, which was absent in sham-pretreated Fischer rats. In contrast, Lewis rats developed cocaine sensitization either with or without corticosterone pretreatment. Thus, both biochemical and behavioral effects of corticosterone observed in Fischer rats were absent in Lewis rats. We next studied the possibility that certain transcription factors, thought to play a role in tyrosine hydroxylase expression, could be involved in these strain-selective effects of corticosterone. Corticosterone treatment decreased levels of glucocorticoid receptor immunoreactivity in the ventral tegmental area of Lewis rats, but not of Fischer rats. In addition, drug-naive Fischer rats showed higher ventral tegmental area levels of immunoreactivity of cyclic AMP response element binding protein than Lewis rats, with no effect of corticosterone observed in either strain.These findings suggest that hypothalamic-pituitary-adrenal axis modulation of responses to drugs of abuse is a genetically determined characteristic seen in Fischer rats, but absent in Lewis rats. We propose that corticosterone administration down-regulates the glucocorticoid receptor in the ventral tegmental area of Lewis rats, and thereby prevents other adaptations to corticosterone treatment, while in the ventral tegmental area of Fischer rats the lack of glucocorticoid receptor down-regulation and the high basal levels of cyclic AMP response element binding protein could facilitate the transcriptional, biochemical and behavioral actions of glucocorticoids.