Damonte Valentina Martinez, Bailey Lydia G, Thakar Amit, Stralka Joanna, Brown Travis E, Kauer Julie A
bioRxiv. 2025 Jun 25:2025.06.23.661181. doi: 10.1101/2025.06.23.661181.
Stress is a potent trigger for drug-seeking behaviors in both rodents and humans with a history of substance use. Kappa opioid receptors (kORs) play a critical role in mediating stress responses. Our previous studies in the ventral tegmental area (VTA) demonstrated that acute stress activates kORs to block long-term potentiation at GABA synapses on dopamine neurons (LTP ) and triggers stress-induced reinstatement of cocaine seeking. Here we identify the specific GABAergic afferents affected by stress, the precise localization of kORs within the VTA, and show that VTA kOR activation is sufficient to drive reinstatement. We optogenetically activated specific GABAergic afferents and found that nucleus accumbens (NAc)-to-VTA, but not lateral hypothalamus (LH)-to-VTA projections, exhibit stress-sensitive LTP . Using a conditional knock-out approach, we found that selectively deleting kORs from NAc neurons but not from dopamine cells prevents stress-induced block of LTP . Selectively activating dynorphin-containing NAc neurons with an excitatory DREADD mimics acute stress, preventing LTP at VTA synapses. We furthermore demonstrated that without acute stress, microinjection of a selective kOR agonist directly into the VTA facilitates cocaine reinstatement without similarly affecting sucrose-motivated responding, demonstrating the critical role of kORs in stress-induced cocaine reinstatement. Our results show that kORs on GABAergic NAc nerve terminals in the VTA underlie loss of LTP that may drive stress-induced addiction-related behaviors. Our work highlights the importance of inhibitory inputs for controlling dopamine neuron excitability in the context of addiction and contributes to defining the circuit involved in stress-induced drug reinstatement.
压力是有药物使用史的啮齿动物和人类寻求药物行为的有力触发因素。κ阿片受体（kORs）在介导应激反应中起关键作用。我们之前在腹侧被盖区（VTA）的研究表明，急性应激激活kORs以阻断多巴胺能神经元上GABA能突触的长时程增强（LTP），并触发应激诱导的可卡因觅药行为恢复。在这里，我们确定了受应激影响的特定GABA能传入神经、kORs在VTA内的精确定位，并表明VTA中kORs的激活足以驱动觅药行为恢复。我们通过光遗传学方法激活特定的GABA能传入神经，发现伏隔核（NAc）到VTA的投射，而非外侧下丘脑（LH）到VTA的投射，表现出应激敏感的LTP。使用条件性敲除方法，我们发现选择性地从NAc神经元而非多巴胺细胞中删除kORs可防止应激诱导的LTP阻断。用兴奋性DREADD选择性激活含强啡肽的NAc神经元可模拟急性应激，阻止VTA突触处的LTP。我们还进一步证明，在没有急性应激的情况下，将选择性kOR激动剂直接微量注射到VTA中可促进可卡因觅药行为恢复，而不会同样影响蔗糖驱动的反应，这表明kORs在应激诱导的可卡因觅药行为恢复中起关键作用。我们的结果表明，VTA中GABA能NAc神经末梢上的kORs是LTP丧失的基础，这可能驱动应激诱导的成瘾相关行为。我们的工作强调了在成瘾背景下抑制性输入对控制多巴胺能神经元兴奋性的重要性，并有助于确定参与应激诱导药物觅药行为恢复的神经回路。
