Pituitary Adenylate Cyclase-Activating Peptide in the Bed Nucleus of the Stria Terminalis Mediates Stress-Induced Reinstatement of Cocaine Seeking in Rats
Pituitary Adenylate Cyclase-Activating Peptide in the Bed Nucleus of the Stria Terminalis Mediates Stress-Induced Reinstatement of Cocaine Seeking in Rats
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DOI：
10.1038/npp.2017.135
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发表时间：
2018-04-01
影响因子：
7.6
通讯作者：
Hammack, Sayamwong E.
中科院分区：
文献类型：
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作者：
Miles, Olivia W.;Thrailkill, Eric A.;Hammack, Sayamwong E.
压力源通常导致在戒断一段时间后难以维持行为改变，并且可能在药物复吸中起重要作用。终纹床核（BNST）中垂体腺苷酸环化酶激活肽（PACAP）系统的激活介导了慢性应激暴露的许多后果。在这里，我们问是否PACAP也参与生产恢复在一个模型中的压力诱导复发吸毒。大鼠自我管理可卡因1小时，每天超过10天，随后进行20天的灭绝训练，其中杠杆按压不再产生可卡因。在实验1中，在几个阶段进行定量PCR（qPCR）以确定PACAP和相应受体的转录水平。恢复可卡因寻求，然后在不同组的大鼠进行了预处理与车辆解决方案，PAC 1受体拮抗剂（实验2），或PACAP激动剂（实验3）没有足电击暴露后进行测试。在实验1中，可卡因自我管理增加BNST PACAP转录水平类似于我们以前报道的慢性应激。在实验2中，内BNST输注的PAC 1/VPAC 2拮抗剂，PACAP 6-38，防止足电击诱导的恢复熄灭可卡因寻求。在实验3中，BNST内PACAP输注恢复先前熄灭可卡因寻求行为的情况下，足电击。可卡因自身给药升高BNST PACAP，并且BNST PACAP受体激活对于可卡因寻求的应激诱导的恢复是必要且充分的。这些数据表明，BNST PACAP系统可能是预防复发的可行靶点。
Stressors often contribute to difficulties in maintaining behavior change following a period of abstinence, and may play a significant role in drug relapse. The activation of pituitary adenylate cyclase-activating peptide (PACAP) systems in the bed nucleus of the stria terminalis (BNST) mediates many consequences of chronic stressor exposure. Here we ask whether PACAP is also involved in producing reinstatement in a model of stress-induced relapse to drug taking. Rats self-administered cocaine for 1 h daily over 10 days that was followed by 20 days of extinction training in which lever pressing no longer produced cocaine. In experiment 1, quantitative PCR (qPCR) was performed at several stages to determine transcript levels of PACAP and corresponding receptors. Reinstatement of cocaine seeking was then tested after footshock exposure in different groups of rats that were pretreated with vehicle solution, a PAC1 receptor antagonist (experiment 2), or a PACAP agonist (experiment 3) without footshock. In experiment 1, cocaine self-administration increased BNST PACAP transcript levels similar to what we have previously reported with chronic stress. In experiment 2, intra-BNST infusions of the PAC1/VPAC2 antagonist, PACAP 6-38, prevented footshock-induced reinstatement of extinguished cocaine seeking. In experiment 3, intra-BNST PACAP infusion reinstated previously extinguished cocaine-seeking behavior in the absence of footshock. Cocaine self-administration elevated BNST PACAP, and BNST PACAP receptor activation was necessary and sufficient for stress-induced reinstatement of cocaine seeking. These data suggest that BNST PACAP systems may be viable targets for relapse prevention.