Aldehyde dehydrogenase 2–associated changes in pharmacokinetics, locomotor function and peripheral glutamic acid and gamma-aminobutyric acid levels during acute alcohol intoxication in male mice

Abstract

The insufficiency of human aldehyde dehydrogenase 2 (ALDH2) has been consistently associated with high blood acetaldehyde levels and impaired locomotor function during acute alcohol intoxication. The ALDH2-associated change in peripheral glutamic acid (Glu) and gamma-aminobutyric acid (GABA) levels and its correlation with pharmacokinetics and psychomotor function remain unclear. In this study, ALDH2*2 mice were used to build an acute alcohol intoxication model after intraperitoneal administration. The blood ethanol and acetaldehyde concentrations were analyzed to generate concentration-time curves at two doses of alcohol (2.0 and 4.0 g/kg). The dose of 4.0 g/kg was selected in accordance with the preliminary behavioral evaluation result to perform the following behavioral tests (e.g. the rotarod test, the open field test, and the Y-maze test), so as to assess locomotor activity, anxiety and cognitive ability. Plasma Glu and GABA levels were determined through enzyme-linked immunosorbent assays. The results suggested that the ALDH2*2 mice had highly accumulated acetaldehyde levels, impaired locomotor activity and anxiety-like emotion but unimpaired cognitive function, compared to the wild type (WT) mice. The plasma Glu level and the ratio of Glu/GABA in the alcohol-treated WT and ALDH2*2 groups decreased from 2 to 5 h after intraperitoneal administration, whereas the GABA level did not change significantly. The blood alcohol concentration in the WT and ALDH2*2 mice was positively correlated with plasma Glu level, whereas the blood acetaldehyde level was found as the opposite. We speculate that the decline degree of Glu/GABA ratio could be associated with psychomotor retardation and needs to be further investigated.

Lipidomic changes of cerebral cortex in aldehyde dehydrogenase-2 knock-in heterozygote mice after chronic alcohol exposure

“…Accordingly, ALDH2*2 mice are an ideal model for the research of human diseases associated with ALDH2 deficiency ( Chen et al, 2014 ). Our previous study also observed the accumulation of acetaldehyde in ALDH2*2 mice after acute alcohol administration, which confirmed the insufficiency of ALDH2 activity ( Li et al, 2022 ).…”

“…Based on anesthesia, approximately 100 μL of the blood sample was collected from the mouse orbital venous sinus and was placed in a heparin sodium anticoagulated EP tube. After 50 μL of blood was prepared by using the optimized PCA method, the ethanol and acetaldehyde concentration in whole blood was determined by Headspace Gas Chromatography coupled with flame ionization ( Xiong et al, 2014 ; Li et al, 2022 ).…”

Analysis of the functional role and mRNA expression of GABABR in the nucleus accumbens of cocaine-addicted rats

“…27 Studies have shown that the Glu/GABA nervous system is closely associated with depression, suicide, and drug addiction. 28 Changes in proteins that regulate Glu transmission are critical for relapse. 29 Animal studies have found that addictive drug abuse leads to increased levels of Glu in the prefrontal cortex, and restraint stress-induced addiction relapse can lead to increased levels of Glu in the prefrontal cortex and striatum, while addictive drugs also have an inhibitory effect on the GABA system.…”