Abbottabad Campus, COMSATS University Islamabad, Abbottabad, Khyber Pakhtunkhawa 22060, Pakistan.
VA San Diego Healthcare System, San Diego, CA 92161, USA.
Int J Mol Sci. 2020 Jun 21;21(12):4411. doi: 10.3390/ijms21124411.
Carbonic anhydrase (CA) is abundant in glial cells in the brain and CA type II isoform (CA II) activity in the hippocampus plays an important role in buffering extracellular pH transients produced by neural activity. Chronic ethanol exposure results in respiratory and metabolic acidosis, producing shifts in extracellular pH in the brain and body. These neurophysiological changes by ethanol are hypothesized to contribute to the continued drinking behavior and physical withdrawal behavior in subjects consuming ethanol chronically. We explored whether chronic ethanol self-administration (ethanol drinking, 10% /; ED) without or under the influence of chronic intermittent ethanol vapor (CIE-ED) experience alters the expression of CA II in the hippocampus. Postmortem hippocampal tissue analyses demonstrated that CA II levels were enhanced in the hilus region of the hippocampus in ED and CIE-ED rats. We used a novel molecule-4-fluoro-N-(4-sulfamoylphenyl) benzenesulfonamide (4-FS)-a selective CA II inhibitor, to determine whether CA II plays a role in ethanol self-administration in ED and CIE-ED rats and physical withdrawal behavior in CIE-ED rats. 4-FS (20 mg/kg, i.p.) reduced ethanol self-administration in ED rats and physical withdrawal behavior in CIE-ED rats. Postmortem hippocampal tissue analyses demonstrated that 4-FS reduced CA II expression in ED and CIE-ED rats to control levels. In parallel, 4-FS enhanced GABA receptor expression, reduced ratio of glutamatergic GluN2A/2B receptors and enhanced the expression of Fos, a marker of neuronal activation in the ventral hippocampus in ED rats. These findings suggest that 4-FS enhanced GABAergic transmission and increased activity of neurons of inhibitory phenotypes. Taken together, these findings support the role of CA II in assisting with negative affective behaviors associated with moderate to severe alcohol use disorders (AUD) and that CA II inhibitors are a potential therapeutic target to reduce continued drinking and somatic withdrawal symptoms associated with moderate to severe AUD.
碳酸酐酶（CA）在大脑中的神经胶质细胞中含量丰富，海马体中的 CA 同工酶 II 型（CA II）活性在缓冲神经活动产生的细胞外 pH 瞬变方面发挥着重要作用。慢性乙醇暴露会导致呼吸和代谢性酸中毒，从而导致大脑和身体的细胞外 pH 发生变化。乙醇引起的这些神经生理学变化被假设为导致慢性摄入乙醇的受试者持续饮酒行为和躯体戒断行为的原因。我们探讨了慢性乙醇自主给药（乙醇饮用，10%/；ED）是否会在慢性间歇性乙醇蒸气（CIE-ED）经历的影响下改变海马体中的 CA II 表达。死后海马组织分析表明，ED 和 CIE-ED 大鼠海马体的齿状回区域 CA II 水平升高。我们使用一种新型分子 4-氟-N-（4-磺酰胺基苯基）苯磺酰胺（4-FS）-一种选择性 CA II 抑制剂，以确定 CA II 是否在 ED 和 CIE-ED 大鼠的乙醇自主给药和 CIE-ED 大鼠的躯体戒断行为中发挥作用。4-FS（20mg/kg，ip）减少 ED 大鼠的乙醇自主给药和 CIE-ED 大鼠的躯体戒断行为。死后海马组织分析表明，4-FS 将 ED 和 CIE-ED 大鼠的 CA II 表达降低至对照水平。平行地，4-FS 增强了 GABA 受体的表达，降低了谷氨酸能 GluN2A/2B 受体的比值，并增强了 ED 大鼠腹侧海马体神经元激活标志物 Fos 的表达。这些发现表明，4-FS 增强了 GABA 能传递，并增加了抑制表型神经元的活性。总之，这些发现支持 CA II 在辅助与中度至重度酒精使用障碍（AUD）相关的负性情感行为中的作用，并且 CA II 抑制剂是减少与中度至重度 AUD 相关的持续饮酒和躯体戒断症状的潜在治疗靶点。
