Ortiz J, DeCaprio J L, Kosten T A, Nestler E J
Department of Psychiatry, Yale University School of Medicine, Connecticut, Mental Health Center, New Haven 06508, USA.
Neuroscience. 1995 Jul;67(2):383-97. doi: 10.1016/0306-4522(95)00018-e.
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.
我们研究了长期给予皮质酮对两种近交系大鼠（Fischer 344和Lewis）的生化和行为影响，这两种大鼠已知在下丘脑 - 垂体 - 肾上腺轴以及对滥用药物的行为反应方面存在差异。首先，我们通过反向磷酸化、二维凝胶电泳和蛋白质免疫印迹分析，研究了皮质酮对假手术组和皮质酮处理组的Fischer和Lewis大鼠腹侧被盖区磷酸化蛋白的调节作用。仅在Fischer大鼠的腹侧被盖区，给予皮质酮上调了酪氨酸羟化酶免疫反应性，并降低了胶质纤维酸性蛋白的磷酸化状态，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致敏的影响，这是一种已知受腹侧被盖区调节的行为。在Fischer大鼠中，慢性皮质酮预处理导致可卡因致敏的出现，而假手术预处理的Fischer大鼠则没有这种情况。相比之下，Lewis大鼠无论有无皮质酮预处理都会出现可卡因致敏。因此，在Fischer大鼠中观察到的皮质酮的生化和行为影响在Lewis大鼠中均未出现。接下来，我们研究了某些被认为在酪氨酸羟化酶表达中起作用的转录因子是否可能参与皮质酮的这些品系选择性效应。皮质酮处理降低了Lewis大鼠腹侧被盖区糖皮质激素受体的免疫反应性水平，但对Fischer大鼠没有影响。此外，未接触过药物的Fischer大鼠腹侧被盖区环磷酸腺苷反应元件结合蛋白的免疫反应性水平高于Lewis大鼠，在这两个品系中均未观察到皮质酮对此有影响。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Fischer大鼠中一种由基因决定的特征，但在Lewis大鼠中不存在。我们提出，给予皮质酮会下调Lewis大鼠腹侧被盖区的糖皮质激素受体，从而阻止对皮质酮处理的其他适应性变化，而在Fischer大鼠的腹侧被盖区，糖皮质激素受体缺乏下调以及环磷酸腺苷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。
