Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels.
Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels.
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DOI：
10.1111/j.1460-9568.2008.06479.x
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发表时间：
2008-11
期刊：
影响因子：
--
通讯作者：
Allison DW
中科院分区：
文献类型：
--
作者：
Steffensen SC;Taylor SR;Horton ML;Barber EN;Lyle LT;Stobbs SH;Allison DW
本研究旨在观察可卡因对腹侧被盖区（VTA）γ-氨基丁酸（GABA）和多巴胺（DA）神经元的影响。利用单单位记录在体内，微电泳管理DA增强放电率VTA GABA神经元通过D2/D3 DA受体激活。较低剂量的静脉注射可卡因（0.25-0.5 mg/kg）或DA转运蛋白（DAT）阻断剂甲基苯丙胺，通过D2/D3受体激活增强VTA GABA神经元放电率。高剂量可卡因（1.0-2.0 mg/kg）可抑制其放电频率，但对D2/D3拮抗剂依替氯必利不敏感。电压敏感性钠通道（VSSC）阻断剂利多卡因在所有测试剂量（0.25-2.0 mg/kg）下均抑制VTA GABA神经元的放电频率。在0.25-2 mg/kg剂量水平（IC 50 1.2 mg/kg）下，可卡因或利多卡因可减少内囊刺激（ICPSD）诱导的VTA GABA神经元尖峰放电。DA或甲基苯丙胺对ICPSD无影响，DA拮抗剂对可卡因抑制ICPSD无影响。在体外培养的VTA GABA神经元中，可卡因以使用依赖的方式减少（IC 50 13 μm）电流诱发的尖峰和TTX敏感的钠电流。在腹侧被盖区DA神经元中，可卡因减少IPSC（IC 50 13 μm），增加IPSC配对脉冲易化，降低自发IPSC频率，而不影响微型IPSC频率或振幅。这些研究结果表明，可卡因作用于GABA神经元，以减少活动依赖性GABA释放的DA神经元在腹侧被盖区，可卡因的使用依赖性封锁腹侧被盖区GABA神经元VSSCs可能协同其DAT抑制性能，以提高中脑边缘DA传输牵连可卡因加固。
The aim of this study was to evaluate the effects of cocaine on γ-aminobutyric acid (GABA) and dopamine (DA) neurons in the ventral tegmental area (VTA). Utilizing single-unit recordings in vivo, microelectrophoretic administration of DA enhanced the firing rate of VTA GABA neurons via D2/D3 DA receptor activation. Lower doses of intravenous cocaine (0.25–0.5 mg/kg), or the DA transporter (DAT) blocker methamphetamine, enhanced VTA GABA neuron firing rate via D2/D3 receptor activation. Higher doses of cocaine (1.0–2.0 mg/kg) inhibited their firing rate, which was not sensitive to the D2/D3 antagonist eticlopride. The voltage-sensitive sodium channel (VSSC) blocker lidocaine inhibited the firing rate of VTA GABA neurons at all doses tested (0.25–2.0 mg/kg). Cocaine or lidocaine reduced VTA GABA neuron spike discharges induced by stimulation of the internal capsule (ICPSDs) at dose levels 0.25–2 mg/kg (IC50 1.2 mg/kg). There was no effect of DA or methamphetamine on ICPSDs, or of DA antagonists on cocaine inhibition of ICPSDs. In VTA GABA neurons in vitro, cocaine reduced (IC50 13 μm) current-evoked spikes and TTX-sensitive sodium currents in a use-dependent manner. In VTA DA neurons, cocaine reduced IPSCs (IC50 13 μm), increased IPSC paired-pulse facilitation and decreased spontaneous IPSC frequency, without affecting miniature IPSC frequency or amplitude. These findings suggest that cocaine acts on GABA neurons to reduce activity-dependent GABA release on DA neurons in the VTA, and that cocaine's use-dependent blockade of VTA GABA neuron VSSCs may synergize with its DAT inhibiting properties to enhance mesolimbic DA transmission implicated in cocaine reinforcement.
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影响因子：
16.2
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通讯作者：
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