Acute Alcohol-Induced Glutamate Changes Measured with Metabotropic Glutamate Receptor 5 Positron Emission Tomography

Background: Alcohol consumption at clinically relevant doses alters brain glutamate release. However, few techniques exist to measure these changes in humans. The metabotropic glutamate receptor 5 (mGluR5) PET radioligand [ ¹¹ C]ABP688 is sensitive to acute alcohol in rodents, possibly mediated by alcohol effects on glutamate release. This study aimed to determine the sensitivity of [ ¹¹ C]ABP688 PET to an acute alcohol challenge in humans. Methods: Eight social drinkers (25–42 years; 5 females) with a recent drinking occasion achieving blood alcohol level (BAL)>80 mg/dL were recruited. All participants underwent a 90-minute dynamic baseline [ ¹¹ C]ABP688 PET scan. Two weeks later (range: 7-29 days), participants completed an oral laboratory alcohol challenge over 30 minutes, targeting a BAL of 60 mg/dL. Immediately after the challenge, a second [ ¹¹ C]ABP688 PET scan was performed. Non-displaceable binding potential ( BP _ND ; indicative of mGluR5 availability) and R ₁ (indicative of relative blood flow) were estimated using the Simplified Reference Tissue Model with the cerebellum as the reference region. Blood samples were taken throughout the scanning procedure to measure the BAL. Results: Seven participants (4 females) completed the study. The mean peak BAL achieved was 61 ± 18 mg/dL. Acute alcohol significantly decreased [ ¹¹ C]ABP688 BP _ND (F(1,42) = 17.05, p < 0.001; Cohen’s d = 0.32–0.60) and increased [ ¹¹ C]ABP688 R ₁ (F(1,42) = 6.67, p = 0.013; Cohen’s d = 0.32–0.48) across brain regions. Exploratory analysis showed a positive relationship between alcohol-induced % change in [ ¹¹ C]ABP688 R ₁ in cortical regions and peak BAL (Spearman rho = 0.78 & 0.85; p = 0.024 & 0.011). Conclusions: This proof-of-concept study demonstrates that [ ¹¹ C]ABP688 PET imaging is sensitive to the effects of acute alcohol consumption. The observed decrease in mGluR5 availability aligns with preclinical data indicating acute increased extracellular glutamate concentrations following ethanol dosing. This imaging tool could be useful for future investigations into the acute effects of alcohol on the brain during abstinence and withdrawal.