Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking.
Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking.
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DOI：
10.1523/jneurosci.1244-10.2010
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发表时间：
2010-06-09
期刊：
影响因子：
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通讯作者：
Kalivas PW
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文献类型：
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作者：
Knackstedt LA;Moussawi K;Lalumiere R;Schwendt M;Klugmann M;Kalivas PW
学习抑制药物寻求可能是抑制复发的重要策略，这可以通过响应药物配对环境而消除药物寻求来模拟。大鼠在没有进行可卡因自我给药的灭绝训练（戒断）的情况下被消灭或撤回，并将伏隔核的核心和外壳亚区室中的突触后密度蛋白的测量结果与轭盐水对照进行比较。只有灭亡的大鼠核心的突触后密度中的 PSD-95、Homer1b/c 和 Narp 升高，而在灭亡或戒断的大鼠中，外壳的突触后密度中测量的蛋白质没有变化。使用生物素化策略，发现 mGluR5 的表面表达仅在死亡动物的核心中减少。虽然熄灭和戒断的动物都表现出通过刺激前额叶皮层在核心引起的长期增强作用的减少，但仅在熄灭的大鼠中观察到长期抑郁的减弱。这些数据表明，核心中 Homer1b/c 的升高可能使 mGluR5 远离膜表面，并且表面 mGluR5 的损失抑制了长期抑制。因此，当荷马1c在携带腺相关病毒的未接触过可卡因的大鼠的核心中过度表达时，长期抑郁症就会受到抑制。这种机制可能有助于通过消退训练抑制可卡因寻求，因为核心中的过度表达 Homer1c 也抑制了提示诱导的可卡因寻求恢复。这些数据确定了一种可能有助于灭绝诱导的可卡因寻求抑制的细胞机制。
Learning to inhibit drug-seeking can be an important strategy for inhibiting relapse, and this can be modeled by extinguishing drug-seeking in response to a drug-paired context. Rats were either extinguished or withdrawn without extinction training (abstinence) from cocaine self-administration and measurements of postsynaptic density proteins in the core and shell subcompartments of the nucleus accumbens were compared to yoked-saline controls. Only extinguished rats had elevations of PSD-95, Homer1b/c, and Narp in the postsynaptic density of the core, while no proteins measured were altered in the postsynaptic density of the shell in either extinguished or abstinent rats. Using a biotinylation strategy, it was found that surface expression of mGluR5 was reduced only in the core of extinguished animals. While both extinguished and abstinent animals showed a reduction in long-term potentiation elicited in the core by stimulating prefrontal cortex, blunted long-term depression was observed only in extinguished rats. These data indicate that the elevation in Homer1b/c in the core may have sequestered mGluR5 away from the membrane surface, and that the loss of surface mGluR5 inhibits long-term depression. Accordingly, when Homer1c was over-expressed in the core of cocaine naïve rats with an adeno-associated virus, long-term depression was inhibited. This mechanism may contribute to the inhibition of cocaine seeking by extinction training because over-expression Homer1c in the core also inhibited cue-induced reinstatement of cocaine seeking. These data identify a cellular mechanism that may contribute to extinction-induced inhibition of cocaine seeking.