摇头丸和冰毒通过不同的机制在中枢蜗牛神经元中引发动作电位爆发。
Ecstasy and methamphetamine elicit action potential bursts via different mechanisms in a central snail neuron.
机构信息
Department of Anesthesiology, National Taiwan University Hospital, Taipei, Taiwan.
出版信息
Neurotoxicology. 2010 Jan;31(1):26-41. doi: 10.1016/j.neuro.2009.11.005. Epub 2009 Dec 1.
This study sought to determine the effects of (+) methamphetamine (METH) and its ring-substituted analog (+/-)3,4-methylenedioxymethamphetamine (MDMA; ecstasy) on electrophysiological behavior and their relationships to second messenger systems in an identifiable RP4 neuron of the African snail, Achatina fulica Ferussac. Extracellular application of MDMA at 1mM and METH at 3mM elicited action potential bursts that were not blocked after immersing the neurons in Ca(2+)-free solution. Notably, MDMA- (1mM) elicited action potential bursts were blocked by pretreatment with the protein kinase C (PKC) inhibitors chelerythrine (20 microM) and Ro 31-8220 (20 microM), but not by the PKA inhibitors KT-5720 (10 microM) and H89 (10 microM). The PKC activator phorbol 12,13-dibutyrate (PDBu; 3 microM), but not the PKA activator forskolin (50 microM), facilitated the induction of bursts elicited by MDMA at a lower concentration (0.3mM). In contrast, METH- (3mM) elicited action potential bursts were blocked by pretreatment with KT-5720 (10 microM) and H89 (10 microM), but not by chelerythrine (20 microM) and Ro 31-8220 (20 microM). Forskolin (50 microM), but not PDBu (3 microM) facilitated the induction of bursts elicited by METH at a lower concentration (1mM). Tetraethylammonium chloride (TEA), a blocker of the delayed rectifying K(+) current (I(KD)), did not elicit bursts at a concentration of 5mM but did facilitate the induction of action potential bursts elicited by both METH and MDMA. Voltage clamp studies revealed that both METH and MDMA decreased the TEA-sensitive I(KD) of the RP4 neuron. Forskolin (50 microM) or dibutyryl cAMP (1mM), a membrane-permeable cAMP analog, alone did not elicit action potential bursts. However, co-administration with forskolin (50 microM) and TEA (5mM) or co-administration with dibutyryl cAMP (1mM) and TEA (50mM) elicited action potential bursts in the presence of the PKC inhibitor chelerythrine (20 microM). Similarly, PDBu (10 microM) or phorbol 12-myristate 13-acetate (PMA; 3 microM) alone did not elicit action potential bursts. However, co-administration with PDBu (10 microM) and TEA (5mM) or co-administration with PMA (3 microM) and TEA (5mM) elicited action potential bursts in the presence of the PKA inhibitor KT-5720 (10 microM). These data suggest that action potential bursts in the RP4 neuron were not due to Ca(2+)-dependent synaptic effects. Rather, action potential bursts may be elicited through (1) combined activation of the cAMP-PKA signaling pathway and inhibition of the I(KD) and (2) combined activation of PKC and inhibition of the I(KD).
本研究旨在确定（+）甲基苯丙胺（METH）及其环状取代类似物（±）3,4-亚甲基二氧基甲基苯丙胺（MDMA；摇头丸）对非洲蜗牛 Achatina fulica Ferussac 中可识别的 RP4 神经元的电生理行为及其与第二信使系统的关系。在将神经元浸入无 Ca2+溶液后，1mM MDMA 和 3mM METH 的细胞外应用会引发动作电位爆发，这些爆发不会被阻断。值得注意的是，MDMA（1mM）引发的动作电位爆发被蛋白激酶 C（PKC）抑制剂 Chelerythrine（20 μM）和 Ro 31-8220（20 μM）预处理阻断，但 PKA 抑制剂 KT-5720（10 μM）和 H89（10 μM）预处理不阻断。PKA 激活剂佛波醇 12,13-二丁酸酯（PDBu；3 μM），而不是 PKA 激活剂 forskolin（50 μM），促进 MDMA 在较低浓度（0.3mM）引发的爆发诱导。相比之下，METH（3mM）引发的动作电位爆发被 KT-5720（10 μM）和 H89（10 μM）预处理阻断，但 Chelerythrine（20 μM）和 Ro 31-8220（20 μM）预处理不阻断。Forskolin（50 μM），而不是 PDBu（3 μM），促进 METH 在较低浓度（1mM）引发的爆发诱导。四乙基氯化铵（TEA），一种延迟整流钾电流（I（KD））的阻断剂，在 5mM 浓度下不会引发爆发，但会促进 METH 和 MDMA 引发的动作电位爆发的诱导。电压钳研究表明，METH 和 MDMA 均降低了 RP4 神经元的 TEA 敏感 I（KD）。单独使用 forskolin（50 μM）或二丁酰环磷酸腺苷（1mM），一种膜通透的 cAMP 类似物，不会引发动作电位爆发。然而，在 PKC 抑制剂 Chelerythrine（20 μM）存在下，与 forskolin（50 μM）和 TEA（5mM）共同给药或与二丁酰环磷酸腺苷（1mM）和 TEA（50mM）共同给药会引发动作电位爆发。同样，单独使用 PDBu（10 μM）或佛波醇 12-肉豆蔻酸 13-醋酸酯（PMA；3 μM）不会引发动作电位爆发。然而，在 PKA 抑制剂 KT-5720（10 μM）存在下，与 PDBu（10 μM）和 TEA（5mM）共同给药或与 PMA（3 μM）和 TEA（5mM）共同给药会引发动作电位爆发。这些数据表明，RP4 神经元中的动作电位爆发不是由于 Ca2+依赖性突触效应引起的。相反，动作电位爆发可能是通过（1）cAMP-PKA 信号通路的联合激活和 I（KD）的抑制以及（2）PKC 的联合激活和 I（KD）的抑制引起的。
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