Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons
Repeated cocaine exposure in vivo facilitates LTP induction in midbrain dopamine neurons
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DOI：
10.1038/nature04050
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发表时间：
2005-10-13
期刊：
影响因子：
64.8
通讯作者：
Poo, MM
中科院分区：
文献类型：
--
作者：
Liu, QS;Pu, L;Poo, MM
众所周知，滥用药物会导致神经回路持续改变，从而导致成瘾行为(1-5)。腹侧被盖区 (VTA) 多巴胺神经元突触可塑性的变化可能有助于许多滥用药物（包括可卡因）引起的回路改变(6-13)。在这里，我们报告，在体内反复接触可卡因后，大鼠 VTA 多巴胺神经元的兴奋性突触变得非常容易受到相关突触前和突触后活动诱导的长时程增强 (LTP) 的影响。这种促进 LTP 诱导的原因是可卡因诱导的 GABA(A)（γ-氨基丁酸）受体介导的对这些多巴胺神经元的抑制作用减少。在用盐水或单剂量可卡因处理的大鼠中脑切片中，VTA 多巴胺神经元中不能诱导 LTP，除非荷包牡丹碱或印防己毒素减少 GABA 介导的抑制作用。然而，在重复使用可卡因治疗的大鼠切片中，LTP 很容易被诱导。通过使用地西泮增强 GABA 介导的抑制作用可以防止这种 LTP 诱导。此外，反复接触可卡因会降低 GABA 介导的突触电流的幅度，并增加 VTA 多巴胺神经元中尖峰启动的可能性。可卡因诱导的 VTA 突触可塑性增强可能对于药物相关记忆的形成很重要。
Drugs of abuse are known to cause persistent modification of neural circuits, leading to addictive behaviours(1-5). Changes in synaptic plasticity in dopamine neurons of the ventral tegmental area (VTA) may contribute to circuit modification induced by many drugs of abuse, including cocaine(6-13). Here we report that, following repeated exposure to cocaine in vivo, excitatory synapses to rat VTA dopamine neurons become highly susceptible to the induction of long-term potentiation (LTP) by correlated pre- and postsynaptic activity. This facilitated LTP induction is caused by cocaine-induced reduction of GABA(A) (gamma-aminobutyric acid) receptor- mediated inhibition of these dopamine neurons. In midbrain slices from rats treated with saline or a single dose of cocaine, LTP could not be induced in VTA dopamine neurons unless GABA-mediated inhibition was reduced by bicuculline or picrotoxin. However, LTP became readily inducible in slices from rats treated repeatedly with cocaine; this LTP induction was prevented by enhancing GABA-mediated inhibition using diazepam. Furthermore, repeated cocaine exposure reduced the amplitude of GABA-mediated synaptic currents and increased the probability of spike initiation in VTA dopamine neurons. This cocaine-induced enhancement of synaptic plasticity in the VTA may be important for the formation of drug-associated memory.