Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N 4N1, Canada.
Hotchkiss Brain Institute, University of Calgary, Calgary AB T2N 4N1, Canada
J Neurosci. 2020 Jul 29;40(31):5894-5907. doi: 10.1523/JNEUROSCI.2049-19.2020. Epub 2020 Jun 29.
The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion-specific manner. However, it is unknown how mu-opioid signaling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using patch-clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist DAMGO produced a concentration-dependent inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV)-expressing interneurons. The DAMGO-induced suppression of inhibition was long lasting and not reversed on washout of DAMGO or by application of the mu-opioid receptor antagonist CTAP, suggesting an inhibitory long-term depression (LTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/protein kinase A (PKA) signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Together, these results suggest that presynaptic mu-opioid stimulation of local PV interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC. Considering that both the orbitofrontal cortex (OFC) and the opioid system regulate reward, motivation, and food intake, understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Second, mu-opioids recruit parvalbumin inputs to suppress inhibitory synaptic transmission in the mOFC. Third, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.
眶额皮层（OFC）在评估不断变化的环境中的结果方面起着关键作用。向 OFC 施用阿片类药物可以改变对食物奖励的享乐反应，并以亚区域特异性的方式增加其消耗。然而，尚不清楚 μ 阿片信号如何影响 OFC 中的突触传递。因此，我们研究了 μ 阿片在 OFC 不同亚区中的细胞作用。使用包含 OFC 的脑片进行膜片钳电生理学研究，我们发现 μ 阿片激动剂 DAMGO 对内侧 OFC（mOFC）神经元的 GABA 能突触传递产生浓度依赖性抑制，但对外侧 OFC（lOFC）神经元没有作用。这种作用是由局部表达钙结合蛋白 Parvalbumin（PV）的中间神经元的突触前 μ 阿片受体激活介导的。DAMGO 诱导的抑制抑制作用持续时间长，在 DAMGO 冲洗或应用 μ 阿片受体拮抗剂 CTAP 时不能逆转，提示外源性 μ 阿片诱导抑制性长时程抑制（LTD）。我们表明，抑制性突触的 LTD 依赖于下游 cAMP/蛋白激酶 A（PKA）信号转导，mOFC 和 lOFC 之间存在差异。最后，我们证明通过适度的生理刺激触发的内源性阿片释放可以诱导 LTD。总之，这些结果表明，局部 PV 中间神经元的突触前 μ 阿片刺激诱导 GABA 能突触传递的持久抑制，这取决于 μ 阿片受体与下游 cAMP/PKA 细胞内级联的偶联的亚区域差异。这些发现为理解 OFC 中 μ 阿片产生的相反功能效应提供了机制上的见解。考虑到眶额皮层（OFC）和阿片系统都调节奖励、动机和食物摄入，了解阿片信号在 OFC 中的作用对于理解几种精神疾病的后果的机制至关重要。本研究有几个新的发现。首先，μ 阿片以区域选择性的方式诱导 OFC 锥体神经元上抑制性突触传递的持久抑制。其次，μ 阿片募集 Parvalbumin 输入以抑制 mOFC 中的抑制性突触传递。第三，内源性阿片类物质的 μ 阿片作用的区域选择性归因于 μ 阿片受体与下游 cAMP/PKA 细胞内级联的偶联效率。这些实验首次揭示了阿片类物质在 OFC 中的细胞作用机制。
