Department of Pharmacology and Toxicology, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
Department of Pharmacology and Toxicology, Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA.
Neuropharmacology. 2014 Feb;77:224-33. doi: 10.1016/j.neuropharm.2013.09.019. Epub 2013 Sep 30.
Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB₁Rs. To directly compare the regional profile of ΔFosB induction and CB₁R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB₁R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB₁R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB₁R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB₁R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB₁R co-localization with ΔFosB in cells and CB₁R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB₁R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB₁R desensitization and/or that ΔFosB induction could be limited by CB₁R desensitization.
重复给予 Δ(9)-四氢大麻酚 (THC) 会导致大脑中大麻素 1 型受体 (CB₁Rs) 脱敏和下调，但这些适应的程度在不同区域有所不同。纹状体及其输出区域的 CB₁Rs 表现出最小的脱敏和下调程度，并且发展最慢。赋予这些区域依赖性差异的分子机制尚不清楚。稳定的转录因子 ΔFosB 在重复给予 THC 后在纹状体中被诱导，并且可以调节 CB₁Rs。为了直接比较 ΔFosB 诱导和 CB₁R 脱敏和下调的区域分布，用 THC（10mg/kg）或载体处理小鼠 13.5 天。CP55,940 刺激的 [(35)S]GTPγS 放射自显影和免疫组织化学分别用于测量 CB₁R 脱敏和下调，通过免疫印迹测量 ΔFosB 表达。在额前皮质、外侧杏仁核和海马体中观察到显著的 CB₁R 脱敏和下调；在基底杏仁核中发现脱敏，而在其余区域未观察到变化。在额前皮质、尾壳核、伏隔核和外侧杏仁核中诱导了 ΔFosB。发现 ΔFosB 表达与 CB₁R 脱敏之间存在反相关系，即具有最大 ΔFosB 诱导的区域没有表现出 CB₁R 脱敏，而没有 ΔFosB 诱导的区域表现出最大的脱敏，其余区域则表现出两者之间的中间水平。纹状体中的双重免疫组织化学显示 CB₁R 与细胞中的 ΔFosB 共定位以及围绕 ΔFosB 阳性细胞的 CB₁R 点状结构。在 CB₁R 敲除小鼠的纹状体中，THC 诱导的 ΔFosB 表达缺失。这些数据表明，ΔFosB 的转录靶标可能抑制 CB₁R 脱敏，或者 ΔFosB 诱导可能受到 CB₁R 脱敏的限制。
