Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca(2+) channels.
Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca(2+) channels.
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DOI：
10.1038/s41380-019-0513-2
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发表时间：
2020-10
影响因子：
11
通讯作者：
Rajadhyaksha AM
中科院分区：
文献类型：
--
作者：
Bavley CC;Fetcho RN;Burgdorf CE;Walsh AP;Fischer DK;Hall BS;Sayles NM;Contoreggi NH;Hackett JE;Antigua SA;Babij R;De Marco García NV;Kash TL;Milner TA;Liston C;Rajadhyaksha AM
可卡因相关记忆是可卡因依赖者复发的关键驱动因素，可以通过暴露于可卡因或压力来诱发。这些环境刺激是否招募类似的分子和电路水平的机制，以促进复发仍然在很大程度上未知。在这里，使用可卡因和压力引发的恢复可卡因条件位置偏好模型药物相关的记忆，我们发现，可卡因驱动恢复的持续时间增加，小鼠在以前的可卡因配对的情况下，而压力增加的条目进入这个上下文中。重要的是，这两种形式的恢复都需要前边缘皮层细胞中的Cav1.2 L型Ca2+通道（LTCC），这些通道投射到丘脑核核心（PrL→NAcC）。利用纤维光度法测量电路活动在体内与LTCC阻滞剂，伊拉地平，我们发现，LTCC驱动差分招聘的PrL→NAcC途径在可卡因和压力引发的恢复。虽然可卡因在进入可卡因配对室之前选择性地激活PrL→NAcC细胞，这是一种预测该室持续时间的措施，但压力增加了这种投射的持续活动，这与进入可卡因配对室有关。使用投射特异性化学遗传学操作，我们表明PrL→NAcC活性是可卡因和应激引发的恢复所必需的，并且Cav1.2缺陷小鼠中这种投射的激活恢复了恢复。这些数据表明，LTCC是可卡因和压力引发的恢复的共同介质。然而，它们参与不同的行为模式和PrL→NAcC投射活动，这取决于环境刺激。这些发现建立了一个框架，以进一步研究不同的环境经历如何驱动复发，并支持进一步探索isradipine，一种FDA批准的LTCC阻滞剂，作为预防可卡因依赖个体复发的潜在治疗药物。
Cocaine-associated memories are critical drivers of relapse in cocaine-dependent individuals that can be evoked by exposure to cocaine or stress. Whether these environmental stimuli recruit similar molecular and circuit-level mechanisms to promote relapse remains largely unknown. Here, using cocaine- and stress-primed reinstatement of cocaine conditioned place preference to model drug-associated memories, we find that cocaine drives reinstatement by increasing the duration that mice spend in the previously cocaine-paired context whereas stress increases the number of entries into this context. Importantly, both forms of reinstatement require Cav1.2 L-type Ca2+ channels (LTCCs) in cells of the prelimbic cortex that project to the nucleus accumbens core (PrL→NAcC). Utilizing fiber photometry to measure circuit activity in vivo in conjunction with the LTCC blocker, isradipine, we find that LTCCs drive differential recruitment of the PrL→NAcC pathway during cocaine- and stress-primed reinstatement. While cocaine selectively activates PrL→NAcC cells prior to entry into the cocaine-paired chamber, a measure that is predictive of duration in that chamber, stress increases persistent activity of this projection, which correlates with entries into the cocaine-paired chamber. Using projection-specific chemogenetic manipulations, we show that PrL→NAcC activity is required for both cocaine- and stress-primed reinstatement, and that activation of this projection in Cav1.2-deficient mice restores reinstatement. These data indicate that LTCCs are a common mediator of cocaine- and stress-primed reinstatement. However, they engage different patterns of behavior and PrL→NAcC projection activity depending on the environmental stimuli. These findings establish a framework to further study how different environmental experiences can drive relapse, and supports further exploration of isradipine, an FDA-approved LTCC blocker, as a potential therapeutic for the prevention of relapse in cocaine-dependent individuals.
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3.4
作者：
Capriles, N;Rodaros, D;Stewart, J
通讯作者：
Stewart, J
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Augur, Isabel F.;Wyckoff, Andrew R.;Peters, Jamie
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FINLAY, JM;ZIGMOND, MJ;ABERCROMBIE, ED
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Krashes, Michael J.;Koda, Shuichi;Lowell, Bradford B.
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