BlackThorn Therapeutics, San Francisco, CA 94103.
UCSF Weill Institute of Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, CA 94143.
eNeuro. 2020 Oct 19;7(5). doi: 10.1523/ENEURO.0376-19.2020. Print 2020 Jul/Aug.
The neuropeptide nociceptin/orphanin FQ (N/OFQ) can be released by stressors and is associated with disorders of emotion regulation and reward processing. N/OFQ and its receptor, NOP, are enriched in dopaminergic pathways, and intra-ventricular agonist delivery decreases dopamine levels in the dorsal striatum, nucleus accumbens (NAc), and ventral tegmental area (VTA). We used whole-cell electrophysiology in acute rat midbrain slices to investigate synaptic actions of N/OFQ. N/OFQ was primarily inhibitory, causing outward currents in both immunocytochemically identified dopaminergic (tyrosine hydroxylase positive (TH(+))) and non-dopaminergic (TH(-)) VTA neurons; effect at 1 μm: 20 ± 4 pA. Surprisingly, this effect was mediated by augmentation of postsynaptic GABAR currents, unlike the substantia nigra pars compacta (SNc), where the N/OFQ-induced outward currents were K channel dependent. A smaller population, 17% of all VTA neurons, responded to low concentrations of N/OFQ with inward currents (10 nm: -11 ± 2 pA). Following 100 nm N/OFQ, the response to a second N/OFQ application was markedly diminished in VTA neurons (14 ± 10% of first response) but not in SNc neurons (90 ± 20% of first response). N/OFQ generated outward currents in medial prefrontal cortex (mPFC)-projecting VTA neurons, but inward currents in a subset of posterior anterior cingulate cortex (pACC)-projecting VTA neurons. While N/OFQ inhibited NAc-projecting VTA cell bodies, it had little effect on electrically or optogenetically evoked terminal dopamine release in the NAc measured with fast scan cyclic voltammetry (FSCV). These results extend our understanding of the N/OFQ system in brainstem circuits implicated in many neurobehavioral disorders.
神经肽孤啡肽/孤啡肽 FQ（N/OFQ）可被应激源释放，并与情绪调节和奖励处理障碍有关。N/OFQ 及其受体 NOP 在多巴胺能通路中丰富，脑室内激动剂的输送会降低背侧纹状体、伏隔核（NAc）和腹侧被盖区（VTA）中的多巴胺水平。我们使用急性大鼠中脑切片的全细胞电生理学研究了 N/OFQ 的突触作用。N/OFQ 主要是抑制性的，导致免疫细胞化学鉴定的多巴胺能（酪氨酸羟化酶阳性（TH(+)))和非多巴胺能（TH(-))) VTA 神经元中的外向电流；在 1μm 时的作用：20±4pA。令人惊讶的是，这种作用是通过增强突触后 GABA 电流介导的，与黑质致密部（SNc）不同，N/OFQ 诱导的外向电流是由 K 通道依赖性的。一小部分（所有 VTA 神经元的 17%）对低浓度的 N/OFQ 产生内向电流（10nm：-11±2pA）。在 100nm N/OFQ 之后，VTA 神经元对第二次 N/OFQ 应用的反应明显减弱（第一次反应的 14±10%），而 SNc 神经元则没有（第一次反应的 90±20%）。N/OFQ 在投射到内侧前额叶皮层（mPFC）的 VTA 神经元中产生外向电流，但在投射到后扣带皮层（pACC）的 VTA 神经元中的一部分中产生内向电流。虽然 N/OFQ 抑制了 NAc 投射的 VTA 胞体，但它对通过快速扫描循环伏安法（FSCV）测量的 NAc 中电或光遗传诱发的终末多巴胺释放几乎没有影响。这些结果扩展了我们对脑干部位涉及许多神经行为障碍的 N/OFQ 系统的理解。
