Acute cocaine exposure occludes long-term depression in ventral tegmental area GABA neurons.
Acute cocaine exposure occludes long-term depression in ventral tegmental area GABA neurons.
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DOI：
10.1016/j.neuint.2021.105002
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发表时间：
2021-05
影响因子：
4.2
通讯作者：
Edwards JG
中科院分区：
文献类型：
--
作者：
Friend LN;Wu B;Edwards JG
中脑腹侧被盖区（VTA）在奖励行为的激励突出中起着至关重要的作用。药物滥用可增加中脑多巴胺细胞活性和/或多巴胺水平，并可改变内源性VTA谷氨酸的可塑性，导致成瘾或依赖。VTA多巴胺细胞受局部抑制性GABA细胞调节，表现出突触前大麻素受体1依赖性谷氨酸能输入的长期抑制。我们目前的目的是确定可卡因对VTA GABA细胞谷氨酸可塑性和回路的影响。采用全细胞电压钳电生理技术对GAD67-GFP敲入小鼠的VTA切片进行记录，记录GABA细胞的兴奋输入。急性和慢性注射可卡因足以阻断长期抑郁。然而，这种可塑性可以逆转到naïve状态，因为在戒断急性可卡因暴露7天后观察到长期抑郁。此外，与车辆注射对照组相比，慢性可卡因降低了AMPA/NMDA比率，多巴胺细胞的变化正好相反。总的来说，我们的数据表明，可卡因介导的突触修饰可能导致依赖/戒断的细胞机制可能涉及VTA多巴胺细胞外谷氨酸输入VTA GABA回路的变化，因此VTA GABA细胞可能在可卡因诱导的整体回路变化中发挥更大的作用，可能以与多巴胺协同的方式发挥作用。
The ventral tegmental area (VTA) in the midbrain is essential in incentive salience of reward behavior. Drugs of abuse increase midbrain dopamine cell activity and/or dopamine levels, and can alter endogenous VTA glutamate plasticity, leading to addiction or dependence. VTA dopamine cells are regulated by local inhibitory GABA cells, which exhibit a form of pre-synaptic cannabinoid receptor 1-dependent long-term depression of their glutamatergic inputs. Our current aim was to determine cocaine’s influence on VTA GABA cell glutamate plasticity and circuity. Using whole cell voltage-clamp electrophysiology in VTA slices of GAD67-GFP knock-in mice, we recorded excitatory inputs on GABA cells. Acute and chronic injections of cocaine were sufficient to occlude long-term depression. The plasticity could be reversed to the naïve state however, as long-term depression was observed following a 7-day abstinence from acute cocaine exposure. Furthermore, chronic cocaine decreased AMPA/NMDA ratios, compared to vehicle injection controls, the opposite change noted in dopamine cells. Collectively, our data suggest the cellular mechanism of cocaine-mediated synaptic modification that may result in dependence/withdrawal could involve changes in glutamate input to VTA GABA circuitry in addition to VTA dopamine cells, and therefore VTA GABA cells may play a larger role, possibly in a synergistic manner with dopamine, in overall cocaine-induced circuit changes than previously known.
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影响因子：
16.2
作者：
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通讯作者：
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