Chronic Ethanol Exposure Disrupts Lactate and Glucose Homeostasis and Induces Dysfunction of the Astrocyte–Neuron Lactate Shuttle in the Brain

Abstract

Background: Impairment of monocarboxylate transporter (MCT)-dependent astrocyte-neuron lactate transfer disrupts long-term memory and erases drug-associated memories in mice. However, few studies have examined how drugs of abuse alter astrocyte-neuron lactate transfer in neurocircuits related to addiction. This is particularly pertinent for ethanol (EtOH), which has been demonstrated to impair central nervious system (CNS) glucose uptake and significantly alter peripheral levels of glucose, lactate, acetate, and ketones.Methods: We subjected C57BL/6J mice to a chronic intermittent EtOH (CIE) exposure paradigm to investigate how chronic EtOH exposure alters the concentration of glucose and lactate within the serum and CNS during withdrawal. Next, we determine how chronic injections of lactate (1 g/kg, twice daily for 2 weeks) influence central and peripheral glucose and lactate concentrations. Finally, we determine how CIE and chronic lactate injection affect astrocyte-neuron lactate transfer by analyzing the expression of MCTs.Results: Our results show that CIE induces lasting changes in CNS glucose and lactate concentrations, accompanied by increased expression of MCTs. Interestingly, although chronic lactate injection mimics the effect of EtOH on CNS metabolites, chronic lactate injection is not associated with increased expression of MCTs.Conclusion: CIE increases CNS concentrations of glucose and lactate and augments the expression of MCTs. Although we found that chronic lactate injection mimics EtOH-induced increases in CNS lactate and glucose, lactate failed to alter the expression of MCTs. This suggests that although lactate may influence the homeostasis of bioenergetic molecules in the CNS, EtOH-associated increases in lactate are not responsible for increased MCT expression.

Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice

“…It is possible that increased brain uptake and utilization of ketone bodies contributed to this, but it is unclear why the effect should be restricted to KME, while ketone levels in the KD group increased over weeks. Interestingly, chronic intermittent alcohol exposure was recently shown to increase brain expression of monocarboxylic acid transporters in mice (Lindberg et al 2019); it is not known whether effects of alcohol and ketosis on monocarboxylic acid transporter expression are additive. If also the case in humans, alcohol-induced monocarboxylic acid transporter upregulation would help brain uptake of ketones in detoxification in patients with AUD.…”

Alcohol-Induced Neuroinflammatory Response and Mitochondrial Dysfunction on Aging and Alzheimer’s Disease

“…The adenosine analog, N6-(4-hydroxybenzyl)-adenosine (NHBA), which activates A2AR and inhibits ENT1, reduced alcohol intake and alcohol reward seeking behavior in mice (Hong et al, 2019 ). Chronic alcohol exposure in mice also alters glucose and lactate concentrations in the brain and decreases the expression of monocarboxylate transporter indicating that alcohol disrupts bioenergetic homeostasis between neurons and glia (Lindberg et al, 2019 ). This suggests impaired alcohol-induced astrocytic-neuronal bioenergetic crosstalk may contribute to impaired energy metabolism seen in AD (Wang et al, 2020 ), and the important roles astrocytes and astrocytic signaling play in the development of AUD.…”

Chronic Alcohol Exposure Induces Aberrant Mitochondrial Morphology and Inhibits Respiratory Capacity in the Medial Prefrontal Cortex of Mice

“…BACs were measured by Analox GL5 multimetabolite analyzer (Analox Instruments, Stourbridge, United Kingdom) with the accompanying kits. The target maximum BAC is about 200 mg ethanol/dl of blood in the vapor chamber, as shown in our previous studies (Lindberg et al, 2019;Starski et al, 2019b). After four cycles of CIA and 8 h of withdrawal, mice were anesthetized with an intraperitoneal injection of ketamine/xylazine (ketamine 100 mg/kg, xylazine 8 mg/kg) and then euthanized via dislocation for Seahorse XF96 Analyzer and western blotting or prefusion for serial block-face scanning electron microscopy (SBFSEM) study.…”