Stress-induced release of dynorphins (Dyn) activates kappa opioid receptors (KOR) in serotonergic neurons to produce dysphoria and potentiate drug reward; however, the circuit mechanisms responsible for this effect are not known. In male mice, we found that conditional deletion of KOR from Slc6a4 (SERT)-expressing neurons blocked stress-induced potentiation of cocaine conditioned place preference (CPP). Within the dorsal raphe nucleus (DRN), two overlapping populations of KOR-expressing neurons: Slc17a8 (VGluT3) and SERT, were distinguished functionally and anatomically. Optogenetic inhibition of these SERT⁺ neurons potentiated subsequent cocaine CPP, whereas optical inhibition of the VGluT3⁺ neurons blocked subsequent cocaine CPP. SERT⁺/VGluT3⁻ expressing neurons were concentrated in the lateral aspect of the DRN. SERT projections from the DRN were observed in the medial nucleus accumbens (mNAc), but VGluT3 projections were not. Optical inhibition of SERT⁺ neurons produced place aversion, whereas optical stimulation of SERT⁺ terminals in the mNAc attenuated stress-induced increases in forced swim immobility and subsequent cocaine CPP. KOR neurons projecting to mNAc were confined to the lateral aspect of the DRN, and the principal source of dynorphinergic (Pdyn) afferents in the mNAc was from local neurons. Excision of Pdyn from the mNAc blocked stress-potentiation of cocaine CPP. Prior studies suggested that stress-induced dynorphin release within the mNAc activates KOR to potentiate cocaine preference by a reduction in 5-HT tone. Consistent with this hypothesis, a transient pharmacological blockade of mNAc 5-HT_1B receptors potentiated subsequent cocaine CPP. 5-HT_1B is known to be expressed on 5-HT terminals in NAc, and 5-HT_1B transcript was also detected in Pdyn⁺, Adora2a⁺ and ChAT⁺ (markers for direct pathway, indirect pathway, and cholinergic interneurons, respectively). Following stress exposure, 5-HT_1B transcript was selectively elevated in Pdyn⁺ cells of the mNAc. These findings suggest that Dyn/KOR regulates serotonin activation of 5HT_1B receptors within the mNAc and dynamically controls stress response, affect, and drug reward.

压力诱导的强啡肽 (Dyn) 释放会激活血清素能神经元中的卡帕阿片受体 (KOR)，从而产生烦躁不安并增强药物奖赏；然而，造成这种效应的电路机制尚不清楚。在雄性小鼠中，我们发现从表达Slc6a4 (SERT) 的神经元中条件性删除 KOR可以阻断应激诱导的可卡因条件性位置偏好 (CPP) 增强。在中缝背核 (DRN) 内，两个重叠的表达 KOR 的神经元群体：Slc17a8 (VGluT3) 和 SERT，在功能和解剖学上进行了区分。这些 SERT ⁺神经元的光遗传学抑制增强了随后的可卡因 CPP，而 VGluT3 ^{+的光抑制}神经元阻断随后的可卡因 CPP。SERT ⁺ /VGluT3 ^-表达神经元集中在 DRN 的侧面。在内侧伏隔核 (mNAc) 中观察到来自 DRN 的 SERT 投影，但未观察到 VGluT3 投影。SERT ⁺神经元的光抑制会产生位置厌恶，而mNAc 中SERT ^{+末端的光刺激会减弱压力引起的强迫游泳不动和随后的可卡因 CPP 的增加。}投射到 mNAc 的 KOR 神经元仅限于 DRN 的侧面，mNAc 中强啡能 (Pdyn) 传入的主要来源来自局部神经元。Pdyn切除mNAc 阻断了可卡因 CPP 的应激增强作用。先前的研究表明，应激诱导的 mNAc 内强啡肽释放会激活 KOR，通过降低 5-HT 音调来增强可卡因偏好。_{与这一假设一致，mNAc 5-HT 1B}受体的短暂药理学阻断增强了随后的可卡因 CPP。已知5-HT _1B在 NAc 的 5-HT 末端表达，并且在Pdyn ⁺、Adora2a ⁺和_ChAT ⁺（分别为直接通路、间接通路和胆碱能中间神经元的标记）中也检测到 5-HT 1B 转录本。压力暴露后，5-HT _1BmNAc 的Pdyn ⁺细胞中转录物选择性升高。这些发现表明，Dyn/KOR 调节mNAc 内5HT _{1B受体的血清素激活，并动态控制应激反应、情感和药物奖励。}