Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

Abstract

During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal.

Keywords: acetate metabolism; alcoholism; glial metabolism; glycolysis; positron emission tomography.

Figure 1.

Alcohol levels in plasma and self-reports for drug effects after placebo (PL) and after alcohol (ALC) for the no-stimulation (NS) and for the video stimulation (VS) conditions in heavy drinkers (HD) and in normal controls (NML). Plasma alcohol concentration did not differ between NML and HD either for NS (A) or VS (B). Alcohol significantly increased self-reports of high and intoxication both for NS (C) and VS (D) but did not increase desire for alcohol. The groups differed only on “Desire for alcohol”, which was significantly higher for HD than NML (C and D, right). Alcohol behavioral effects did not differ between groups.

Figure 2.

Effects of alcohol on brain glucose metabolism in NMLs and HDs. A, SPM results showing areas where the absolute metabolic measures were significantly reduced by alcohol compared with placebo (PL > ALC) for the NS and the VS in NMLs and HDs at p_FWE < 0.005. B, Histogram showing regions where effects of alcohol where greater during NS than VS.

Figure 3.

Differences in baseline brain glucose metabolism (placebo measures) between NMLs and HDs. A, SPM results showing areas where metabolism was significantly greater for NMLs than HDs (NML > HD) at p_FWE < 0.0001. B, Histogram showing brain metabolism in BA 18 and BA 22 for the placebo conditions; these areas also showed greater metabolic values in NMLs than HDs.

Figure 4.

Effects of VS on brain glucose metabolism (absolute metabolic images) compared with NS during placebo (PL) and alcohol intoxication (ALC). A, SPM results showing areas where metabolism was greater for VS > NS for significance p_FWE < 0.05. There were no areas where metabolism was greater for NS than for VS. B, Histograms showing the differences (VS vs NS) in metabolic rates in BA 18 and BA 22, for the combined PL and ALC for NMLs and HDs.

Figure 5.

Effects of VS on relative metabolic images (normalized to whole-brain metabolism) during placebo (PL) and alcohol intoxication (ALC). A, SPM results showing areas where “relative metabolism” was greater for VS > NS for significance p_FWE < 0.05. B, Histograms showing “relative” metabolic values in BA 18 and BA 22, for NMLs and for HDs, during the PL and ALC conditions.

Figure 6.

Simplified model for the interpretation of our findings. In sobriety, glia and neurons predominantly rely on glucose as energy substrate for metabolism at rest and during stimulation, both through aerobic glycolysis and through oxidative phosphorylation. During alcohol intoxication (acute alcohol), when acetate levels in plasma increase, glial cells increase their reliance on acetate metabolism as energy source to sustain resting activity. In HDs, the reliance of glial cells on acetate to sustain resting activity is enhanced and persists beyond intoxication, which could contribute to their low resting brain glucose metabolic rates during sobriety but also their larger decrements in brain glucose metabolism during intoxication.