Moriguchi Shigeki, Watanabe Shigenori, Kita Hitoshi, Nakanishi Hiroshi
Graduate School of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Exp Brain Res. 2002 May;144(2):238-46. doi: 10.1007/s00221-002-1039-3. Epub 2002 Mar 15.
It has been suggested that behavioral methamphetamine sensitization involves changes in cortical excitatory synaptic inputs to neostriatal (Str) projection neurons. To test this, we performed blind whole-cell recording of medium spiny neurons in Str slice preparations. In Str neurons of naive rats, the amplitude of the subcortical white matter stimulation-induced N-methyl- D-aspartate receptor-mediated excitatory postsynaptic potentials (NMDA-EPSPs) was decreased upon hyperpolarization, owing to the voltage-dependent Mg(2+) blockade of NMDA receptor channels. In contrast, the amplitude of the NMDA-EPSPs in Str neurons of rats undergoing methamphetamine withdrawal (MW) did not show the Mg(2+) blockade and was nearly voltage independent over the membrane potential range of -70 to -110 mV. Application of the specific protein kinase C (PKC) activator, phorbol 12, 13- DL-acetate, blocked the voltage-dependent Mg(2+) blockade of NMDA receptor channels in Str neurons of naive rats. Application of the specific activator of cAMP-dependent protein kinase A (PKA), Sp-cAMPS-triethylamine salt, increased the amplitude of the NMDA receptor-mediated EPSPs at the rest but not at hyperpolarized potentials. Coapplication of the PKC and PKA activators yielded NMDA-EPSPs similar to those seen in Str neurons of MW rats. In Str slices of naive rats, tetanic subcortical white matter stimulation induced long-term depression of field potentials. In Str slices treated with the PKC and/or PKA, the same stimulation induced long-term potentiation of field potentials similar to those observed in slices obtained from MW rats. These results suggest that the enhancement of the NMDA receptor-mediated corticostriatal synaptic transmission plays an important role in behavioral methamphetamine sensitization. This enhancement is probably associated with phosphorylation of NMDA receptors mediated by the simultaneous activation of PKC and PKA.
有观点认为，行为性甲基苯丙胺敏感化涉及新纹状体（Str）投射神经元的皮质兴奋性突触输入的变化。为了验证这一点，我们在Str脑片制备中对中等棘状神经元进行了盲法全细胞记录。在未接触过甲基苯丙胺的大鼠的Str神经元中，由于NMDA受体通道的电压依赖性Mg(2+)阻断，皮层下白质刺激诱导的N-甲基-D-天冬氨酸受体介导的兴奋性突触后电位（NMDA-EPSPs）的幅度在超极化时降低。相比之下，经历甲基苯丙胺戒断（MW）的大鼠的Str神经元中，NMDA-EPSPs的幅度没有显示出Mg(2+)阻断，并且在-70至-110 mV的膜电位范围内几乎与电压无关。应用特异性蛋白激酶C（PKC）激活剂佛波醇12,13 - 二肉豆蔻酸酯可阻断未接触过甲基苯丙胺的大鼠的Str神经元中NMDA受体通道的电压依赖性Mg(2+)阻断。应用环磷酸腺苷依赖性蛋白激酶A（PKA）的特异性激活剂Sp-cAMPS-三乙胺盐可增加静息时但不是超极化电位时NMDA受体介导的EPSPs的幅度。PKC和PKA激活剂共同应用产生的NMDA-EPSPs与MW大鼠的Str神经元中观察到的相似。在未接触过甲基苯丙胺的大鼠的Str脑片中，强直皮层下白质刺激诱导场电位的长时程抑制。在用PKC和/或PKA处理的Str脑片中，相同的刺激诱导场电位的长时程增强，类似于在从MW大鼠获得的脑片中观察到的。这些结果表明，NMDA受体介导的皮质纹状体突触传递的增强在行为性甲基苯丙胺敏感化中起重要作用。这种增强可能与PKC和PKA同时激活介导的NMDA受体磷酸化有关。
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