Role of orbitofrontal cortex neuronal ensembles in the expression of incubation of heroin craving.
Role of orbitofrontal cortex neuronal ensembles in the expression of incubation of heroin craving.
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DOI：
10.1523/jneurosci.1914-12.2012
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发表时间：
2012-08-22
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影响因子：
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通讯作者：
Hope BT
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作者：
Fanous S;Goldart EM;Theberge FR;Bossert JM;Shaham Y;Hope BT
在人类中，接触到以前与海洛因使用有关的线索往往会在长时间戒断后引发复发。在大鼠中，线索诱导的海洛因寻找在戒断后逐渐增加(海洛因渴望的孵化)。在这里，我们研究了眼眶额叶皮质(OFC)神经元在海洛因长期戒断或海洛因渴求潜伏期表达后对海洛因线索的增强反应中的作用。训练大鼠自行给药(6h/d，连续10d)，并在戒断1d或14d后进行消退试验。线索诱导的海洛因寻求从1d增加到14d，并伴有~12%的OFC神经元Fos表达增加。用GABA激动剂baclofen+Muscimol非选择性地灭活OFC神经元，可在戒断第14天减少线索诱导的海洛因寻找，但不能减少第1天。然后，我们使用Daun02失活程序评估少数选择性激活的表达Fos的OFC神经元(可能形成编码线索的神经元群)在线索诱导的海洛因寻找中的因果作用。我们训练CFOS-LacZ转基因大鼠自我给药海洛因，11天后再次暴露于海洛因相关线索或新线索15分钟(诱导日)，90分钟后注射OFC Daun02或车辆；3天后进行消退试验。Daun02选择性地减少了先前在诱导日再次暴露于海洛因相关线索的大鼠的线索诱导的海洛因寻找，但不减少先前暴露于新线索的大鼠的海洛因寻找。结果提示，海洛因线索激活的OFC神经元群参与了海洛因渴求的潜伏期表达。
In humans, exposure to cues previously associated with heroin use often provokes relapse after prolonged withdrawal periods. In rats, cue-induced heroin-seeking progressively increases after withdrawal (incubation of heroin craving). Here, we examined the role of orbitofrontal cortex (OFC) neuronal ensembles in the enhanced response to heroin cues after prolonged withdrawal or the expression of incubation of heroin craving. We trained rats to self-administer heroin (6-h/d for 10 d) and assessed cue-induced heroin-seeking in extinction tests after 1 or 14 withdrawal days. Cue-induced heroin-seeking increased from 1 day to 14 days and was accompanied by increased Fos expression in ~12% of OFC neurons. Non-selective inactivation of OFC neurons with the GABA agonists baclofen+muscimol decreased cue-induced heroin-seeking on withdrawal day 14 but not day 1. We then used the Daun02 inactivation procedure to assess a causal role of the minority of selectively activated Fos-expressing OFC neurons (that presumably form cue-encoding neuronal ensembles) in cue-induced heroin-seeking after 14 withdrawal days. We trained cfos-lacZ transgenic rats to self-administer heroin and 11 days later re-exposed them to heroin-associated cues or novel cues for 15 min (induction day) followed by OFC Daun02 or vehicle injections 90 min later; we then tested the rats in extinction tests 3 days later. Daun02 selectively decreased cue-induced heroin-seeking in rats previously re-exposed to the heroin-associated cues on induction day, but not in rats previously exposed to novel cues. Results suggest that heroin-cue-activated OFC neuronal ensembles contribute to the expression of incubation of heroin craving.