Polter Abigail M, Barcomb Kelsey, Chen Rudy W, Dingess Paige M, Graziane Nicholas M, Brown Travis E, Kauer Julie A
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, United States.
Neuroscience Program, University of Wyoming, Laramie, United States.
Elife. 2017 Apr 12;6:e23785. doi: 10.7554/eLife.23785.
Stressful experiences potently activate kappa opioid receptors (κORs). κORs in the ventral tegmental area regulate multiple aspects of dopaminergic and non-dopaminergic cell function. Here we show that at GABAergic synapses on rat VTA dopamine neurons, a single exposure to a brief cold-water swim stress induces prolonged activation of κORs. This is mediated by activation of the receptor during the stressor followed by a persistent, ligand-independent constitutive activation of the κOR itself. This lasting change in function is not seen at κORs at neighboring excitatory synapses, suggesting distinct time courses and mechanisms of regulation of different subsets of κORs. We also provide evidence that constitutive activity of κORs governs the prolonged reinstatement to cocaine-seeking observed after cold water swim stress. Together, our studies indicate that stress-induced constitutive activation is a novel mechanism of κOR regulation that plays a critical role in reinstatement of drug seeking.
应激经历能有效激活κ阿片受体（κORs）。腹侧被盖区的κORs调节多巴胺能和非多巴胺能细胞功能的多个方面。在此，我们表明，在大鼠腹侧被盖区多巴胺能神经元的GABA能突触处，单次短暂冷水游泳应激会诱导κORs的长期激活。这是由应激源期间受体的激活介导的，随后κOR自身会发生持续的、不依赖配体的组成性激活。在相邻兴奋性突触的κORs处未观察到这种功能的持久变化，这表明不同亚群的κORs具有不同的时间进程和调节机制。我们还提供证据表明，κORs的组成性活性控制着冷水游泳应激后观察到的对可卡因寻求行为的长期恢复。总之，我们的研究表明，应激诱导的组成性激活是κOR调节的一种新机制，在药物寻求行为的恢复中起关键作用。
