Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, USA.
Neuropsychopharmacology. 2017 Aug;42(9):1800-1812. doi: 10.1038/npp.2017.22. Epub 2017 Jan 31.
Alcohol abuse disorders are associated with dysfunction of frontal cortical areas including the orbitofrontal cortex (OFC). The OFC is extensively innervated by monoamines, and drugs that target monoamine receptors have been used to treat a number of neuropsychiatric diseases, including alcoholism. However, little is known regarding how monoamines affect OFC neuron excitability or whether this modulation is altered by chronic exposure to ethanol. In this study, we examined the effect of dopamine, norepinephrine, and serotonin on lOFC neuronal excitability in naive mice and in those exposed to chronic intermittent ethanol (CIE) treatment. All three monoamines decreased current-evoked spike firing of lOFC neurons and this action required G-coupled D2, α2-adrenergic, and 5HT receptors, respectively. Inhibition of firing by dopamine or the D2 agonist quinpirole, but not norepinephrine or serotonin, was prevented by the GABA receptor antagonist picrotoxin. GABA-mediated tonic current was enhanced by dopamine or the D1 agonist SKF81297 but not quinpirole, whereas the amplitude of spontaneous IPSCs was increased by quinpirole but not dopamine. Spiking was also inhibited by the direct GIRK channel activator ML297, whereas blocking these channels with barium increased firing and eliminated the inhibitory actions of monoamines. In the presence of ML297 or the G-protein blocker GDP-β-S, DA induced a further decrease in spike firing, suggesting the involvement of a non-GIRK channel mechanism. In neurons from CIE-treated mice, spike frequency was nearly doubled and inhibition of firing by monoamines or ML297 was lost. These effects occurred in the absence of significant changes in expression of G or GIRK channel proteins. Together, these findings show that monoamines are important modulators of lOFC excitability and suggest that disruption of this process could contribute to various deficits associated with alcohol dependence.
酒精滥用障碍与额皮质区域（包括眶额皮质（OFC））的功能障碍有关。OFC 广泛接受单胺的神经支配，靶向单胺受体的药物已被用于治疗多种神经精神疾病，包括酒精中毒。然而，对于单胺如何影响 OFC 神经元兴奋性，或者这种调节是否会因慢性暴露于乙醇而改变，人们知之甚少。在这项研究中，我们检查了多巴胺、去甲肾上腺素和 5-羟色胺对幼稚小鼠和慢性间歇性乙醇（CIE）处理小鼠 lOFC 神经元兴奋性的影响。这三种单胺都降低了 lOFC 神经元的电流诱发放电，这种作用分别需要 G 偶联的 D2、α2-肾上腺素能和 5HT 受体。D2 激动剂喹吡罗抑制放电，但不是去甲肾上腺素或 5-羟色胺，可被 GABA 受体拮抗剂胡椒碱预防。多巴胺或 D1 激动剂 SKF81297 增强了 GABA 介导的紧张性电流，但不是喹吡罗，而喹吡罗增加了自发 IPSC 的幅度，但不是多巴胺。直接 GIRK 通道激活剂 ML297 也抑制了放电，而用钡阻断这些通道则增加了放电并消除了单胺的抑制作用。在 ML297 或 G 蛋白阻滞剂 GDP-β-S 的存在下，DA 诱导了 Spike 放电的进一步减少，这表明涉及非 GIRK 通道机制。在 CIE 处理小鼠的神经元中， Spike 频率几乎增加了一倍，单胺或 ML297 对放电的抑制作用丧失。这些效应发生在 G 或 GIRK 通道蛋白表达没有明显变化的情况下。总之，这些发现表明单胺是 lOFC 兴奋性的重要调节剂，并表明该过程的中断可能导致与酒精依赖相关的各种缺陷。
