Long-lasting change in brain dynamics induced by methamphetamine: enhancement of protein kinase C-dependent astrocytic response and behavioral sensitization
Long-lasting change in brain dynamics induced by methamphetamine: enhancement of protein kinase C-dependent astrocytic response and behavioral sensitization
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DOI：
10.1111/j.1471-4159.2005.03097.x
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发表时间：
2005-06-01
影响因子：
4.7
通讯作者：
Suzuki, T
中科院分区：
文献类型：
--
作者：
Narita, M;Miyatake, M;Suzuki, T
众所周知，长期接触精神刺激剂会诱导神经元可塑性。近年来，越来越多的证据表明，星形胶质细胞可能积极参与突触的可塑性。在这项研究中，我们发现在体外用甲基苯丙胺(METH)或吗啡(MRP)处理皮质神经元/神经胶质细胞可通过蛋白激酶C(PKC)激活星形胶质细胞。冰毒对纯化的星形胶质细胞有明显的激活作用，而MRP则无此作用。在皮质神经元/胶质细胞共培养中，METH，而不是MRP，引起了长期的星形胶质细胞激活。此外，间歇给药后停药2个月后，MRP诱导的对超运动的行为敏感化被逆转，而对冰毒诱导的超运动的行为敏感化即使在停药2个月后仍保持不变。与这项细胞培养研究一致的是，与行为敏化相关的冰毒体内处理导致小鼠扣带皮质和伏隔核中PKC依赖的星形胶质细胞激活。这些发现提供了直接证据，表明冰毒通过刺激啮齿动物大脑中的PKC而诱导持久的星形胶质细胞激活和行为敏化。相反，MRP通过神经元PKC产生可逆的星形胶质细胞激活和行为敏化的可逆性。这一信息可以打破滥用药物的定义，以及吗啡产生长期神经毒性的误导概念。
It is well known that long-term exposure to psychostimulants induces neuronal plasticity. Recently, accumulating evidence suggests that astrocytes may actively participate in synaptic plasticity. In this study, we found that in vitro treatment of cortical neuron/glia co-cultures with either methamphetamine (METH) or morphine (MRP) caused the activation of astrocytes via protein kinase C (PKC). Purified astrocytes were markedly activated by METH, whereas MRP had no such effect. METH, but not MRP, caused a long-lasting astrocytic activation in cortical neuron/glia co-cultures. Furthermore, MRP-induced behavioral sensitization to hyper-locomotion was reversed by 2 months of withdrawal following intermitted MRP administration, whereas behavioral sensitization to METH-induced hyper-locomotion was maintained even after 2 months of withdrawal. Consistent with this cell culture study, in vivo treatment with METH, which was associated with behavioral sensitization, caused a PKC-dependent astrocytic activation in the cingulate cortex and nucleus accumbens of mice. These findings provide direct evidence that METH induces a long-lasting astrocytic activation and behavioral sensitization through the stimulation of PKC in the rodent brain. In contrast, MRP produced a reversible activation of astrocytes via neuronal PKC and a reversibility of behavioral sensitization. This information can break through the definition of drugs of abuse and the misleading of concept that morphine produces a long-lasting neurotoxicity.