Beitner-Johnson D, Guitart X, Nestler E J
Department of Pharmacology, Yale University School of Medicine, Connecticut Mental Health Center, New Haven 06508.
J Neurosci. 1992 Jun;12(6):2165-76. doi: 10.1523/JNEUROSCI.12-06-02165.1992.
The ventral tegmental area (VTA) and its dopaminergic projections appear to mediate some of the rewarding properties of opiates, cocaine, and other drugs of abuse. In a previous study, we demonstrated that chronic morphine and cocaine exert common actions on tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, in this dopaminergic brain reward region (Beitner-Johnson and Nestler, 1991). In the present study, we investigated the effects of chronic morphine and cocaine on other phosphoproteins in the VTA by back phosphorylation and two-dimensional electrophoretic analysis. It was found that a number of phosphoproteins, in addition to tyrosine hydroxylase, were regulated similarly by the two drug treatments in this brain region. Several of these morphine- and cocaine-regulated phosphoproteins were identified as neurofilament (NF) proteins. Chronic, but not acute, administration of either morphine or cocaine was found to decrease levels of the three NF proteins, NF-200 (NF-H), NF-160 (NF-M), and NF-68 (NF-L), by between 15% and 50% in the VTA by back phosphorylation, immunolabeling, and Coomassie blue staining. Such regulation of NF proteins was selective, in that no detectable changes were observed in the levels of eight other major cytoskeletal or cytoskeletal-associated proteins analyzed. Furthermore, NF levels were not altered by chronic treatment with either imipramine or haloperidol, two psychotropic drugs without reinforcing properties, or by chronic stress. Morphine and cocaine regulation of NFs showed regional specificity, as NF levels were not altered in the substantia nigra, or other parts of the brain or spinal cord, by these drug treatments. NFs are thought to function as determinants of neuronal morphology and to be associated with axonal transport. Thus, decreased NF levels in the VTA in response to chronic morphine and chronic cocaine could lead to drug-induced alterations in the structural and functional properties of this brain region, which may represent, in turn, part of a common biochemical basis of morphine and cocaine addiction and craving.
腹侧被盖区（VTA）及其多巴胺能投射似乎介导了阿片类药物、可卡因和其他滥用药物的一些奖赏特性。在之前的一项研究中，我们证明了慢性吗啡和可卡因对该多巴胺能脑奖赏区域中儿茶酚胺生物合成的限速酶酪氨酸羟化酶具有共同作用（Beitner-Johnson和Nestler，1991）。在本研究中，我们通过反向磷酸化和二维电泳分析研究了慢性吗啡和可卡因对VTA中其他磷蛋白的影响。结果发现，除酪氨酸羟化酶外，该脑区中许多磷蛋白受这两种药物处理的调节方式相似。这些受吗啡和可卡因调节的磷蛋白中有几种被鉴定为神经丝（NF）蛋白。通过反向磷酸化、免疫标记和考马斯亮蓝染色发现，慢性给予吗啡或可卡因（而非急性给予）会使VTA中三种NF蛋白，即NF-200（NF-H）、NF-160（NF-M）和NF-68（NF-L）的水平降低15%至50%。NF蛋白的这种调节具有选择性，因为在所分析的其他八种主要细胞骨架或细胞骨架相关蛋白的水平上未观察到可检测到的变化。此外，慢性给予丙咪嗪或氟哌啶醇（两种无强化特性的精神药物）或慢性应激均未改变NF水平。吗啡和可卡因对NF的调节具有区域特异性，因为这些药物处理并未改变黑质、大脑或脊髓其他部位的NF水平。NF被认为是神经元形态的决定因素，并与轴突运输有关。因此，VTA中NF水平因慢性吗啡和慢性可卡因而降低可能导致该脑区结构和功能特性的药物诱导改变，这反过来可能代表吗啡和可卡因成瘾及渴望的共同生化基础的一部分。
