The Nociceptin/Orphanin FQ (N/OFQ) peptide and its receptor NOP are highly expressed within several regions of the mesolimbic system, including the ventral tegmental area (VTA). Evidence indicates that the N/OFQ-NOP receptor system is involved in reward processing and historically it has been proposed that activation of NOP receptors attenuates the motivation for substances of abuse. However, recent findings demonstrated that drug self-administration and relapse to drug-seeking are also attenuated after administration of NOP receptor antagonists. Here, to shed light on the mechanisms through which NOP receptor blockers modulate these processes, we utilized patch-clamp recordings to investigate the effect of the selective NOP receptor antagonist LY2817412 on VTA dopaminergic (DA) function in male rats. Results showed that, similar to the endogenous NOP receptor agonist N/OFQ, LY2817412 reduced the spontaneous basal firing discharge of VTA DA neurons. Consistently, we found that NOP receptors are expressed both in VTA DA and GABA cells and that LY2817412 slice perfusion increased GABA release onto VTA DA cells. Finally, in the attempt to dissect the role of postsynaptic and presynaptic NOP receptors, we tested the effect of N/OFQ and LY2817412 in the presence of GABA receptors blockers. Results showed that the effect of LY2817412 was abolished following pretreatment with GABAR, but not GABAR, blockers. Conversely, inhibition of DA neuronal activity by N/OFQ was unaffected by blockade of GABA receptors. Altogether, these results suggest that both NOP receptor agonists and antagonists can decrease VTA DA neuronal activity, but through distinct mechanisms of action. The effect of NOP receptor antagonists occurs through a GABAR-mediated mechanism while NOP receptor agonists seem to act via a direct effect on VTA DA neurons.

中文翻译：

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NOP 受体的药理学阻断通过 GABAB 受体介导的机制降低腹侧被盖区多巴胺神经元活性

伤害感受肽/孤啡宁 FQ (N/OFQ) 肽及其受体 NOP 在中脑边缘系统的多个区域高度表达，包括腹侧被盖区 (VTA)。有证据表明，N/OFQ-NOP 受体系统参与奖励处理，历史上有人提出，NOP 受体的激活会减弱滥用药物的动机。然而，最近的研究结果表明，服用 NOP 受体拮抗剂后，药物自我给药和复发寻药也会减弱。在这里，为了阐明 NOP 受体阻滞剂调节这些过程的机制，我们利用膜片钳记录来研究选择性 NOP 受体拮抗剂 LY2817412 对雄性大鼠 VTA 多巴胺能 (DA) 功能的影响。结果显示，与内源性 NOP 受体激动剂 N/OFQ 类似，LY2817412 减少 VTA DA 神经元的自发基础放电。一致地，我们发现 NOP 受体在 VTA DA 和 GABA 细胞中都有表达，并且 LY2817412 切片灌注增加了 GABA 释放到 VTA DA 细胞上。最后，为了剖析突触后和突触前 NOP 受体的作用，我们测试了 N/OFQ 和 LY2817412 在 GABA 受体阻滞剂存在下的作用。结果显示，用 GABAR（而非 GABAR 阻滞剂）预处理后，LY2817412 的作用被消除。相反，N/OFQ 对 DA 神经元活性的抑制不受 GABA 受体阻断的影响。总而言之，这些结果表明 NOP 受体激动剂和拮抗剂都可以降低 VTA DA 神经元活性，但作用机制不同。NOP 受体拮抗剂的作用是通过 GABAR 介导的机制发生的，而 NOP 受体激动剂似乎是通过直接作用于 VTA DA 神经元来发挥作用。