Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, Oregon, USA.
J Pharmacol Exp Ther. 2012 May;341(2):455-63. doi: 10.1124/jpet.111.190595. Epub 2012 Feb 14.
Neuroadaptations underlying sensitization to drugs of abuse seem to influence compulsive drug pursuit and relapse associated with addiction. Our previous data support a role for the corticotropin-releasing factor (CRF) type-1 receptor (CRF₁) in ethanol (EtOH)-induced psychomotor sensitization. CRF₁ is endogenously activated by CRF and urocortin-1. Because genetic deletion of urocortin-1 did not affect EtOH sensitization, we hypothesized that CRF is the important ligand underlying EtOH sensitization. To test this hypothesis, we used heterozygous and homozygous knockout (KO) mice, which lack one or both copies of the gene coding for CRF, and their respective wild-type controls. EtOH sensitization was normal in heterozygous, but absent in homozygous, CRF KO mice. Corticosterone (CORT) levels were drastically reduced only in CRF KO mice. Because CRF/CRF₁ initiate EtOH-induced activation of the hypothalamic-pituitary-adrenal axis, we investigated CORT effects on EtOH sensitization. The CORT synthesis inhibitor metyrapone prevented the acquisition, but not the expression, of EtOH sensitization. Exogenous CORT administration sensitized the locomotor response to a subsequent EtOH challenge; we observed, however, that the exogenous CORT levels necessary to induce sensitization to EtOH were significantly higher than those produced by EtOH treatment. Therefore, participation of CORT seems to be necessary, but not sufficient, to explain the role of CRF/CRF₁ in the acquisition of sensitization to EtOH. Extra-hypothalamic CRF/CRF₁ mechanisms are suggested to be involved in the expression of EtOH sensitization. The present results are consistent with current theories proposing a key role for CRF and CRF₁ in drug-induced neuroplasticity, dependence, and addictive behavior.
药物滥用敏化的神经适应似乎会影响与成瘾相关的强迫性药物追求和复发。我们之前的数据支持促肾上腺皮质释放因子 (CRF) 1 型受体 (CRF₁) 在乙醇 (EtOH) 诱导的运动敏化中的作用。CRF₁ 被 CRF 和尿皮质素-1 内源性激活。由于尿皮质素-1 的基因缺失不影响 EtOH 敏化，我们假设 CRF 是 EtOH 敏化的重要配体。为了验证这一假设，我们使用了杂合子和纯合子敲除 (KO) 小鼠，它们缺乏编码 CRF 的基因的一个或两个拷贝，以及各自的野生型对照。杂合子 EtOH 敏化正常，但纯合子 CRF KO 小鼠则不存在。皮质酮 (CORT) 水平仅在 CRF KO 小鼠中大幅降低。由于 CRF/CRF₁ 启动 EtOH 诱导的下丘脑-垂体-肾上腺轴的激活，我们研究了 CORT 对 EtOH 敏化的影响。CORT 合成抑制剂美替拉酮可阻止 EtOH 敏化的获得，但不能阻止其表达。外源性 CORT 给药敏化了随后 EtOH 挑战的运动反应；然而，我们观察到，诱导 EtOH 敏化所需的外源性 CORT 水平明显高于 EtOH 处理产生的水平。因此，CORT 的参与似乎是必需的，但不足以解释 CRF/CRF₁ 在 EtOH 敏化获得中的作用。建议涉及额外下丘脑的 CRF/CRF₁ 机制在 EtOH 敏化的表达中起作用。目前的结果与当前的理论一致，即 CRF 和 CRF₁ 在药物诱导的神经可塑性、依赖和成瘾行为中起关键作用。
