Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

Abstract

It has been reported that chronic and acute alcohol exposure decreases cerebral glucose metabolism and increases acetate oxidation. However, it remains unknown how much ethanol the living brain can oxidize directly and whether such a process would be affected by alcohol exposure. The questions have implications for reward, oxidative damage, and long-term adaptation to drinking. One group of adult male Sprague-Dawley rats was treated with ethanol vapor and the other given room air. After 3 wk the rats received i.v. [2-13 C]ethanol and [1, 2-13 C 2 ]acetate for 2 h, and then the brain was fixed, removed, and divided into neocortex and subcortical tissues for measurement of 13 C isotopic labeling of glutamate and glutamine by magnetic resonance spectroscopy. Ethanol oxidation was seen to occur both in the cortex and the subcortex. In ethanol-naïve rats, cortical oxidation of ethanol occurred at rates of 0.017 ± 0.002 μmol/min/g in astroglia and 0.014 ± 0.003 μmol/min/g in neurons, and chronic alcohol exposure increased the astroglial ethanol oxidation to 0.028 ± 0.002 μmol/min/g (P = 0.001) with an insignificant effect on neuronal ethanol oxidation. Compared with published rates of overall oxidative metabolism in astroglia and neurons, ethanol provided 12.3 ± 1.4% of cortical astroglial oxidation in ethanol-naïve rats and 20.2 ± 1.5% in ethanol-treated rats. For cortical astroglia and neurons combined, the ethanol oxidation for naïve and treated rats was 3.2 ± 0.3% and 3.8 ± 0.2% of total oxidation, respectively. 13C labeling from subcortical oxidation of ethanol was similar to that seen in cortex but was not affected by chronic ethanol exposure.T he liver is the major organ for the oxidation of ethanol (Etoh) (1, 2), followed by the stomach and other organs. Acetate (Ac) generated from Etoh by the liver is consumed by the brain (3, 4), where it replaces a significant portion of cerebral glucose metabolism in humans and animals (5-8), either decreasing glucose consumption directly or compensating for glucose consumption decreased by some other effect. However, the brain may also oxidize Etoh (9-14), and that capacity is important with respect to several perspectives. The first step of Etoh oxidation generates acetaldehyde (AA), which is toxic, reactive, and potentially carcinogenic. AA is aversive systemically, as has been observed from the unpleasant effects of disulfuram, an inhibitor of AA dehydrogenase, but it has been shown to be rewarding in parts of the brain (12,15,16) especially in the posterior ventral tegmental area (17-19) by activating dopamine neurons (20)(21)(22). The liver maintains circulating levels of AA at levels of 20-155 μM (23, 24), and AA has been reported not to penetrate the blood-brain barrier or to penetrate very slowly (23,25). Thus, if the brain can oxidize Etoh, then intracerebral AA may mediate behavioral, neurochemical, and toxic effects of Etoh in the brain, possibly playing a role in the development of alcohol dependence (6,16,26).AA is difficult to measure in living systems. The ...

The Neurometabolic Fingerprint of Excessive Alcohol Drinking

“…Deficits in energy metabolism have also been reported for morphine addiction (Chen et al, 2007;Yang et al, 2007;Deng et al, 2012). Alternatively, alcohol at relevant pharmacological doses is known to shift substrate utilization in the brain away from glucose toward acetate oxidation (Volkow et al, 2006(Volkow et al, , 2013Wang et al, 2013). However, these changes were observed after an acute alcohol challenge and are thus difficult to compare with the present observations from 3-day abstinent rats.…”

Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations

“…At the higher end of estimates, others have suggested that ethanol contributes up to 12% of total astroglial metabolism (Wang et al . ); with estimates for the contribution of astroglial metabolism estimated using acetate as around 17% of total brain metabolism, this arrives at an estimate of around 2% of total brain metabolism being supplied by ethanol.…”

Alcohol affects brain functional connectivity and its coupling with behavior: greater effects in male heavy drinkers

“…Relative to light drinkers, heavy drinkers show lower resting CBF, 19 particularly within the frontal lobe, 20 and lower resting CMRglc, possibly due to higher acetate metabolism. 13, 21, 22 In summary, it is difficult to determine the extent to which effects of acute and chronic alcohol exposure on CBF and CMRglc reflect exclusive changes in neuronal activity.…”