Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Pharmaceutical Sciences, University of Vienna, Vienna, 1090, Austria.
Neurobiol Dis. 2024 Sep;199:106590. doi: 10.1016/j.nbd.2024.106590. Epub 2024 Jul 10.
The infralimbic cortex (IL) is part of the medial prefrontal cortex (mPFC), exerting top-down control over structures that are critically involved in the development of alcohol use disorder (AUD). Activity of the IL is tightly controlled by γ-aminobutyric acid (GABA) transmission, which is susceptible to chronic alcohol exposure and withdrawal. This inhibitory control is regulated by various neuromodulators, including 5-hydroxytryptamine (5-HT; serotonin). We used chronic intermittent ethanol vapor inhalation exposure, a model of AUD, in male Sprague-Dawley rats to induce alcohol dependence (Dep) followed by protracted withdrawal (WD; 2 weeks) and performed ex vivo electrophysiology using whole-cell patch clamp to study GABAergic transmission in layer V of IL pyramidal neurons. We found that WD increased frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs), whereas miniature IPSCs (mIPSCs; recorded in the presence of tetrodotoxin) were unaffected by either Dep or WD. The application of 5-HT (50 μM) increased sIPSC frequencies and amplitudes in naive and Dep rats but reduced sIPSC frequencies in WD rats. Additionally, 5-HT receptor antagonist M100907 and 5-HT receptor antagonist SB242084 reduced basal GABA release in all groups to a similar extent. The blockage of either 5-HT or 5-HT receptors in WD rats restored the impaired response to 5-HT, which then resembled responses in naive rats. Our findings expand our understanding of synaptic inhibition in the IL in AUD, indicating that antagonism of 5-HT and 5-HT receptors may restore GABAergic control over IL pyramidal neurons. SIGNIFICANCE STATEMENT: Impairment in the serotonergic modulation of GABAergic inhibition in the medial prefrontal cortex contributes to alcohol use disorder (AUD). We used a well-established rat model of AUD and ex vivo whole-cell patch-clamp electrophysiology to characterize the serotonin modulation of GABAergic transmission in layer V infralimbic (IL) pyramidal neurons in ethanol-naive, ethanol-dependent (Dep), and ethanol-withdrawn (WD) male rats. We found increased basal inhibition following WD from chronic alcohol and altered serotonin modulation. Exogenous serotonin enhanced GABAergic transmission in naive and Dep rats but reduced it in WD rats. 5-HT and 5-HT receptor blockage in WD rats restored the typical serotonin-mediated enhancement of GABAergic inhibition. Our findings expand our understanding of synaptic inhibition in the infralimbic neurons in AUD.
扣带皮层（IL）是内侧前额叶皮层（mPFC）的一部分，对在酒精使用障碍（AUD）发展中起关键作用的结构施加自上而下的控制。IL 的活动受到γ-氨基丁酸（GABA）传递的严格控制，而这种传递易受慢性酒精暴露和戒断的影响。这种抑制控制受到各种神经调质的调节，包括 5-羟色胺（5-HT；血清素）。我们使用慢性间歇性乙醇蒸气吸入暴露，这是一种 AUD 模型，在雄性 Sprague-Dawley 大鼠中诱导酒精依赖（Dep），随后进行长期戒断（WD；2 周），并使用全细胞膜片钳进行离体电生理学研究，以研究 IL 锥体神经元中第五层的 GABA 能传递。我们发现 WD 增加了自发性抑制性突触后电流（sIPSCs）的频率，而微 IPSC（在使用河豚毒素的情况下记录）不受 Dep 或 WD 的影响。5-HT（50 μM）的应用增加了幼稚和 Dep 大鼠中 sIPSC 的频率和幅度，但降低了 WD 大鼠中 sIPSC 的频率。此外，5-HT 受体拮抗剂 M100907 和 5-HT 受体拮抗剂 SB242084 以相似的程度减少了所有组中的基础 GABA 释放。在 WD 大鼠中阻断 5-HT 或 5-HT 受体恢复了对 5-HT 的受损反应，然后类似于幼稚大鼠的反应。我们的发现扩展了我们对 AUD 中 IL 中的突触抑制的理解，表明拮抗 5-HT 和 5-HT 受体可能恢复对 IL 锥体神经元的 GABA 能控制。
5-羟色胺能调制内侧前额叶皮层 GABA 抑制的损害导致酒精使用障碍（AUD）。我们使用了一种成熟的大鼠 AUD 模型和离体全细胞膜片钳电生理学，以表征乙醇幼稚、乙醇依赖（Dep）和乙醇戒断（WD）雄性大鼠中第五层扣带皮层（IL）锥体神经元中 GABA 能传递的 5-羟色胺调制。我们发现慢性酒精戒断后基础抑制增加，并改变了 5-羟色胺的调制。外源性 5-HT 增强了幼稚和 Dep 大鼠中的 GABA 能传递，但在 WD 大鼠中减少了传递。WD 大鼠中 5-HT 和 5-HT 受体的阻断恢复了典型的 5-HT 介导的 GABA 抑制增强。我们的发现扩展了我们对 AUD 中扣带神经元中突触抑制的理解。
