Amphetamine blocks long-term synaptic depression in the ventral tegmental area
Amphetamine blocks long-term synaptic depression in the ventral tegmental area
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DOI：
10.1523/jneurosci.20-15-05575.2000
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发表时间：
2000-08-01
影响因子：
5.3
通讯作者：
Kauer, JA
中科院分区：
文献类型：
--
作者：
Jones, S;Kornblum, JL;Kauer, JA
中脑边缘多巴胺系统对于奖赏寻求行为是必不可少的，滥用药物被认为会篡夺这一途径的正常功能。越来越多的证据表明，腹侧被盖区（VTA）的多巴胺神经元上的多巴胺能突触在暴露于成瘾药物期间被修改，产生敏化，精神兴奋剂药物的奖励特性随着重复暴露而逐渐增强。我们已经测试了这一假设，即精神兴奋剂暴露干扰突触可塑性的腹侧被盖区的多巴胺能输入。我们发现腹侧被盖区多巴胺神经元上的兴奋性突触对低频刺激和适度的去极化表现出长时程抑制（LTD）。LTD在腹侧被盖区是NMDA受体非依赖性的，但依赖于细胞内Ca 2+，并可通过驱动Ca 2+进入多巴胺神经元而诱导。短暂接触安非他明完全阻断LTD在腹侧被盖区的多巴胺能突触，通过释放内源性多巴胺，作用于D2多巴胺受体。我们在腹侧被盖区发现的LTD很可能是奖赏通路兴奋性控制的重要组成部分;安非他明将抑制LTD，消除对多巴胺神经元的多巴胺能驱动的正常制动。安非他明的这种作用代表了一种重要的机制，通过这种机制，大脑奖赏系统的正常功能可能在药物滥用期间受到损害。
The mesolimbic dopamine system is essential for reward-seeking behavior, and drugs of abuse are thought to usurp the normal functioning of this pathway. A growing body of evidence suggests that glutamatergic synapses on dopamine neurons in the ventral tegmental area (VTA) are modified during exposure to addictive drugs, producing sensitization, a progressive augmentation in the rewarding properties of psychostimulant drugs with repeated exposure. We have tested the hypothesis that psychostimulant exposure interferes with the synaptic plasticity of glutamatergic inputs to the VTA. We find that excitatory synapses onto VTA dopamine neurons exhibit long-term depression (LTD) in response to low-frequency stimulation and modest depolarization. LTD in the VTA is NMDA receptor-independent but is dependent on intracellular Ca2+ and can be induced by driving Ca2+ into the dopamine neuron. Brief exposure to amphetamine entirely blocks LTD at glutamatergic synapses in the VTA, by releasing endogenous dopamine that acts at D2 dopamine receptors. The block of LTD is selective, because amphetamine has no effect on hippocampal LTD. The LTD we have discovered in the VTA is likely to be an important component of excitatory control of the reward pathway; amphetamine will inhibit LTD, removing this normal brake on the glutamatergic drive to dopamine neurons. This effect of amphetamine represents an important mechanism by which normal function of the brain reward system may be impaired during substance abuse.