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

doi:10.21203/rs.3.rs-5183167/v1

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

https://doi.org/10.21203/rs.3.rs-5183167/v1

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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 [¹¹C]ABP688 is sensitive to acute alcohol in rodents, possibly mediated by alcohol effects on glutamate release. This study aimed to determine the sensitivity of [¹¹C]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 [¹¹C]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 [¹¹C]ABP688 PET scan was performed. Non-displaceable binding potential (BP_ND; indicative of mGluR5 availability) and R₁ (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 [¹¹C]ABP688 BP_ND (F(1,42) = 17.05, p < 0.001; Cohen’s d = 0.32–0.60) and increased [¹¹C]ABP688 R₁ (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 [¹¹C]ABP688 R₁ 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 [¹¹C]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.

Cellular & Molecular Neuroscience

metabotropic glutamate type 5 receptors

positron emission tomography

alcohol challenge

glutamate release

social drinkers

Glutamate is the primary excitatory neurotransmitter in the mammalian brain, playing a central role in physiological processes such as learning, memory, and neuroplasticity. Dysregulated glutamate signaling is reported with both acute and chronic alcohol exposure¹. Ethanol has dose-related effects on extracellular limbic glutamate levels in rats with doses associated with social drinking (0.5 g/kg) elevating extracellular glutamate levels, while much higher levels (2.0 g/kg) reducing these levels². In models of binge-like consumption^3–5, alcohol initially raises extracellular glutamate levels in, but then glutamate release levels drop below baseline as blood alcohol levels (BAL) decline^2,6,7. Chronic alcohol exposure has been associated with excessive extracellular glutamate levels and excitatory signaling^7–10. Importantly, disrupted glutamate signaling has been associated with craving and relapse propensity during abstinence¹¹. While ethanol effects on brain glutamate release in rodents seems important, limited tools exist to measure changes in glutamate release in people¹².

Studies have shown that positron emission tomography (PET) imaging with the radiotracer [¹¹C]ABP688 [3-((6-methylpyridin-2-yl)ethynyl) cyclohex-2-en-1-one-O-[¹¹C]methyloxime] is sensitive to changes in extracellular glutamate levels. [¹¹C]ABP688 binds selectively to the allosteric site of metabotropic type 5 glutamate receptors (mGluR5)^13,14, which are excitatory Gq-coupled G protein receptors predominantly expressed on the postsynaptic sites of neurons¹⁵. Acute administration of ketamine, which transiently elevates glutamate levels, reduces [¹¹C]ABP688 volumes of distribution (V_T)^16,17, supporting use of [¹¹C]ABP688 PET to measure changes in extracellular glutamate concentrations. A recent rodent study used simultaneous microdialysis and [¹¹C]ABP688 microPET imaging to show concurrent increases in glutamate release and decreases in striatal [¹¹C]ABP688 binding following administration of ethanol¹⁸. This is consistent with prior reports of calcium-dependent glutamate release in the rodent brain following ethanol administration^2,6,7,19. In animals, at doses higher than typically seen with social drinking (EC₅₀ ~ 200 mM), ethanol inhibits mGluR5 function by promoting PKC-related phosphorylation²⁰. Motivated by these findings, the goal of this study was to translate these findings to people by evaluating the mGluR5 response to an acute laboratory alcohol challenge with [¹¹C]ABP688 and PET. The hypothesis for this study was that acute alcohol consumption would decrease mGluR5 availability in the brain. A secondary goal was to evaluate the acute alcohol effects on relative [¹¹C]ABP688 delivery (R₁), a surrogate of relative blood flow with other radiotracers^21,22, as acute alcohol is known to increase blood flow^23–25. The findings establish a novel imaging tool to measure alcohol-induced glutamate fluctuations in the human brain.

Recruitment and Study Participants

The Yale School of Medicine Human Investigation Committee and the Radiation Safety Committee approved all procedures. Study participants were recruited from the local New Haven population. Participants self-reported at least a single drinking occasion sufficient to reach an estimated BAL of 80 mg/dL in the past three months, operationally defined as more than three drinks for females and more than four drinks for males at intake. This ensured that study participants had prior drinking experience consistent with levels achieved in this study. Participants were asked to recall the two heaviest days of drinking in the previous three months, useful for calculating the BAL achieved for those episodes.

Prior to their participation, all subjects provided written informed consent. Recruited participants had no current or past significant medical or neurological disorders, did not meet DSM-5 criteria for current or past psychiatric or substance use disorder. Subjects who had a history of perceptual distortions, seizures, delirium, or hallucinations upon alcohol withdrawal or scored > 12 on the Clinical Institute Withdrawal Assessment scale at intake appointments was excluded. Additionally, participants did not use psychotropic medication over the month prior to participation. Participants medically contraindicated to consuming alcohol were also excluded. Negative pregnancy tests were required for all females during screening and on the day of radiotracer administration. During intake and on scan day, alcohol drinking over the prior 30 days was recorded with the Alcohol Timeline Followback Interview²⁶. A total of eight social drinkers (five women and three men) were recruited to participate (see Results and Table 1 for demographics). One subject met criteria for mild AUD.

Experimental Design

All subjects participated in two [¹¹C]ABP688 PET scans and a laboratory alcohol drinking session (see Fig. 1). Participants were asked to abstain from alcohol for at least 48 hours prior to the study day, confirmed by self-report. Abstinence on the morning of scanning was confirmed with a negative breath alcohol test. Baseline [¹¹C]ABP688 PET scans were acquired on the ‘Baseline Day’. Two to three weeks after the Baseline Day, participants came in for the ‘Alcohol Challenge Day’. The Alcohol Challenge Day started with a standardized lunch. Next, at approximately 12:00 pm, participants consumed an alcohol dose calculated to achieve a BAL of at least 60 mg/dL. The dose was prepared taking into account the participant’s total body water (based on sex, age, height, and weight), duration of drinking, and ratio of alcohol to mixer, based on Watson et al. 's update of the Widmark Eq. 2⁷. Alcohol was administered as 80-proof vodka mixed with a decarbonated, non-caffeinated, and non-caloric drink of the participant’s choice at a 1:3 alcohol-to-mixer ratio. The total volume was divided into three equal drinks, with each consumed over a 10-minute period to pace the rate of consumption, requiring 30 minutes for completion. Immediately after the completion of the laboratory alcohol session, the post-alcohol [¹¹C]ABP688 PET scan was acquired. To avoid the diurnal effects of [¹¹C]ABP688²⁸, PET scans were scheduled at the same time on different days (approximately 12:30 pm).

The Biphasic Alcohol Effects Scale (BAES)²⁹ and Drug Effects Questionnaire (DEQ)³⁰ were used to assess the subjective effects of alcohol. BAES is a 14-item questionnaire on an 11-point scale measuring alcohol's stimulating and sedating effects. DEQ, a 5-item visual analog scale, evaluates the subjective effects of alcohol, and includes items assessing FEEL and HIGH drug effect. BAES was measured at baseline (roughly five minutes prior to the start of the alcohol session), and every 30 minutes after the start of the alcohol session for at least 180 minutes after the start of the alcohol session. DEQ was measured at baseline, and every 15 minutes until at least 45 minutes after the start of the alcohol session.

To measure BAL, venous blood samples were acquired at 30-min intervals from the start of the alcohol drinking session until the end of the scanning routine, including a baseline sample approximately 5 min before the start of the session. BAL was measured with headspace gas chromatography at the Yale-New Haven Hospital Clinical Laboratories using their standard protocol.

Imaging data acquisition

[¹¹C]ABP688 of high E/Z ratio (70:1)¹⁶ was synthesized at the Yale PET Center as previously described³¹, resulting in high molar activities of 420 ± 129 GBq/µmol (minimum = 299 GBq/µmol). PET data were acquired with a High Resolution Research Tomograph (Siemens Medical Solutions USA, Inc., Malvern, PA, USA). Head motion data were acquired with an optical motion-tracking tool (Vicra; NDI Systems, Waterloo, ON, Canada). A six-minute transmission scan was acquired for attenuation correction prior to the radiotracer injection. PET data acquisition began simultaneously with the administration of [¹¹C]ABP688 as a slow bolus over one minute. Dynamic PET data were acquired for 90 minutes alongside arterial blood sampling to measure the metabolite-corrected input function¹⁶.

On a separate day, all participants underwent T1-weighted structural magnetic resonance (MR) scans, acquired with a Siemens 3.0T scanner (Siemens Medical Solutions USA, Inc., Malvern, PA, USA) equipped with a 64-channel head coil, providing high-resolution anatomical maps for PET data coregistration. A sagittal gradient-echo MPRAGE sequence was employed (FOV: 256 × 256 mm², 176 slices at 1 mm thickness, TE: 2.77 ms, TR: 2530 ms, TI: 1100 ms, FA: 7°).

Preprocessing and Kinetic modeling

Dynamic list-mode brain PET data were binned into discrete time frames of increasing length up to five minutes and reconstructed with the MOLAR algorithm³². The first ten minutes of PET brain data were registered to the subject-specific T1-weighted MRI using a mutual information algorithm with six degrees of freedom (FLIRT, FSL 3.2; Analysis Group; FMRIB, Oxford, UK). To define the regions of interest, the native MRI was co-registered to the Montreal Neurological Institute template space with a nonlinear transformation algorithm (BioImage Suite; http://www.bioimagesuite.com). Time-activity curves were generated from the frontal cortex, temporal cortex, striatum, hippocampus, and cerebellum. These regions were chosen due to their known involvement in glutamate neurotransmission and their relevance to the neurobiological effects of alcohol. Regions of interest were gray matter masked as assessed by CAT (A Computational Anatomy Toolbox for Statistical Parametric Mapping [SPM12; Institute of Neurology, University College of London, London, England]; Jena University Hospital, Jena, Germany).

For a subset of the participants (n = 4, 2 males, 2 females), arterial blood samples were collected throughout both the scanning procedures. [¹¹C]ABP688 volumes of distribution (V_T) were calculated in the selected regions, including the cerebellum. V_T is the ratio of [¹¹C]ABP688 concentration in tissue to [¹¹C]ABP688 concentration in arterial plasma at equilibrium and was estimated with the two tissue compartment model (2TCM). However, arterial blood sampling was not available for both scans in three participants, leading us to primarily use [¹¹C]ABP688 non-displaceable binding potential (BP_ND) as the outcome measure for this study. BP_ND provides a measure of receptor availability in the brain regions, indicating the density of available receptors in relation to non-displaceable binding.

BP _ND and R₁ were estimated using the Simplified Reference Tissue Model³⁴ with the cerebellum as the reference region. While the cerebellum is commonly used as a reference region due to its minimal specific binding^35,36, there is evidence for small amounts of mGluR5-specific binding, which could bias BP_ND estimates (see Discussion). R₁ values, defined as the ratio of rate constants (K₁) describing tracer influx from plasma to the target region and to the reference region, were also estimated. The R₁ value quantifies relative radiotracer delivery to different brain regions. Since [¹¹C]ABP688 has high first-pass extraction³⁷, R₁ provides a proxy measure of relative blood flow as complements to BP_ND analyses, providing a more comprehensive understanding of the acute effects of alcohol on brain function.

Statistical analysis

Separate linear mixed-effect models were employed for the statistical analysis of [¹¹C]ABP688 BP_ND and R₁, following confirmation of the data's normal distribution. The constructed model incorporated PET state (baseline vs. post-alcohol) and Region as fixed effects, along with their interaction, while a random intercept accounted for individual variability (PatientID). Post hoc pairwise comparisons (Fisher’s Least Significant Difference) were utilized to determine the impact of alcohol on the frontal cortex, temporal cortex, hippocampus, and striatum.

Alcohol-induced ΔBP_ND and ΔR₁ were quantified as percentage differences ([Post-alcohol – Baseline]/Baseline * 100). Exploratory analyses examined potential relationships between ΔBP_ND and ΔR₁ with the following factors: (1) subjective alcohol effects, (2) peak BAL, and (3) self-reported alcohol consumption over the past month. These analyses were designed to test hypotheses concerning the mGluR5 response to alcohol: (1) its association with subjective alcohol responses, (2) its dependence on alcohol dosage, and (3) its correlation with recent drinking history. Subjective effects analyses focused on stimulation during the ascending limb (30-minute intervals of BAES stimulation, DEQ FEEL, and DEQ HIGH) and sedation during the descending limb (150-minute and 210-minute intervals of BAES sedation). Further partial correlation analyses, controlling for baseline subjective effects, were conducted to explore the associations between ΔBP_ND and ΔR₁ and BAL measures, as well as recent drinking history. Given the exploratory nature of these analyses, Spearman rank correlation coefficients (Spearman’s rho) were calculated without correction for multiple comparisons.

Scan characteristic and V_T value comparisons were made using paired t-tests. Statistical analyses were performed using R 4.2.2 (“Innocent and Trusting”) and RStudio (RStudio Team, Boston, MA, USA), with data visualization carried out using GraphPad Prism (v. 9.4.1; GraphPad Software, San Diego, CA, United States).

Participant demographics and characteristics

Table 1

Participant demographics and scanning parameters
Age	27.7 ± 6 years (range: 22–42)
Sex	3M; 4F
Number of drinks in the last 30 days on Scan Day	22 ± 20 drinks (range: 2–53)
AUD status (DSM-5)	1 Mild AUD (1F)
Peak BAL	61 ± 18 mg/dL (n = 7)
Days between scan	17 ± 8 days (range: 7–29)
Injected dose	Baseline: 614.5 ± 62 MBq (range: 530–684)
Injected dose	Post-alcohol: 638 ± 53 MBq (range: 529–688)
Injected mass	Baseline: 0.36 ± 0.1 µg (range: 0.19–0.43)
Injected mass	Post-alcohol: 0.39 ± 0.1 µg (range: 0.27–0.54)
Scan Start Time of Dat	Baseline: 12:17 (range: 11:55 − 12:35)
Scan Start Time of Dat	Post-alcohol: 12:24 (range: 11:59 − 12:36)
Abbreviations: AUD, Alcohol Use Disorder; F, female; M, male; No significant differences were noted in the [¹¹C]ABP688 injected dose or mass.

Eight participants (3 males, 5 females) enrolled in the study. One female met DSM-5 criteria for mild alcohol use disorder. One participant did not complete the study, vomiting during the laboratory alcohol session, with a peak BAL of 33 mg/dL at 120 minutes. This participant was excluded from the final analysis. The final analysis included seven participants (3 males, 4 females) with an average age of 27.7 ± 6 years. These participants reported consuming an average of 22 ± 20 drinks in the last 30 days. During the laboratory drinking session, males consumed 150.7 ± 11 mL of 80-proof alcohol, while females consumed 111.6 ± 20 mL. The average peak BAL among the included participants was 61.4 ± 18 mg/dL, exhibiting a typical biphasic BAL curve (see Fig. 2). Behavioral data indicated that alcohol consumption led to a decrease in stimulation and increase in sedation, as measured by the BAES, and in subjective feelings of intoxication, as FEEL and HIGH measured by the DEQ (Supp. Figure 1). For PET scans, no significant differences were observed in injected activity, injected mass, or the time of scan between the baseline and post-alcohol scans (Table 1).

Using the Cerebellum as a reference region

Analysis of [¹¹C]ABP688 V_T was restricted to the four people for which arterial input function was acquired for both scans (see Supp. Table. 1). The cerebellum exhibited little change from baseline (1.95 ± 0.4; range = 1.66–2.44) compared with post-alcohol (2.03 ± 0.3; range = 1.71–2.46), with an overall change of 4.5 ± 4% (range = 0.07–8.58%), within the reported cerebellum [¹¹C]ABP688 V_T test-retest variability of 13%²⁸. This result was taken to support use of the cerebellum as a reference region for this study design.

Acute alcohol decreases brain mGluR5 availability

Brain mGluR5 availability, quantified by [¹¹C]ABP688 BP_ND, significantly decreased post-alcohol compared to baseline. The main effect of alcohol (F(1,42) = 17.05, p < 0.001) was statistically significant. The interaction between alcohol and region was not statistically significant (F(4,42) = 0.57, p = 0.632), suggesting that the decrease in mGluR5 availability was potentially a whole-brain effect. On average, [¹¹C]ABP688 BP_ND values decreased by 9% post-alcohol compared to baseline, as illustrated in Fig. 3. Post hoc analysis revealed moderate effect sizes of alcohol in the following brain regions: frontal cortex (9.08% decrease, Cohen’s d = 0.49, p = 0.015), temporal cortex (11.2% decrease, Cohen’s d = -0.60, p = 0.010), striatum (8.9% decrease, Cohen’s d = -0.49, p = 0.021), and hippocampus (6.6% decrease, Cohen’s d = -0.32, p = 0.317).

Relative blood flow, quantified by [¹¹C]ABP688 R₁, significantly increased post-alcohol compared to baseline. The main effect of alcohol (F(1,42) = 6.69, p = 0.013) was statistically significant, while the interaction between alcohol and region was not statistically significant (F(4,42) = 0.08, p = 0.970). Exploratory post hoc analysis revealed a significant increase in the striatum (2.59% increase, Cohen’s d = 0.46, p = 0.046) but no significant changes in the frontal cortex, hippocampus, or temporal cortex (see Fig. 2).

Relationship of [ ¹¹ C]ABP688 mGluR5 availability and relative blood flow with peak BAL, recent drinking behavior, and subjective effects

Exploratory analyses revealed no significant relationships between ΔBP_ND and peak BAL, past month number of drinks, or subjective effects such as BAES or DEQ. In contrast, there was initial evidence for significant (uncorrected for multiple comparisons) poasitive relationships between ΔR₁ and peak BAL in frontal cortex (Spearman rho = 0.85; p = 0.011) and temporal cortex (Spearman rho = 0.78; p = 0.024), as illustrated in Fig. 5. No other significant relationships were found between ΔR₁ and peak BAL, recent drinking amounts, or subjective effects like BAES or DEQ (Supp. Tables 2 and 3).

This study reveals evidence that a laboratory alcohol challenge achieving an average peak BAL of ~ 60 mg/dL significantly reduced brain mGluR5 availability, as measured by [¹¹C]ABP688 BP_ND. Further analyses yielded modest evidence that alcohol increased relative blood flow in cortical regions, as measured by [¹¹C]ABP688 R₁, with positive correlations between R₁ increases and peak BAL, largely confirming prior findings. No significant associations were found between post-alcohol ΔBP_ND or ΔR₁ and recent drinking behavior or subjective effects. The findings establish a novel imaging paradigm for investigating the dynamic effects of acute alcohol on brain glutamate function.

This in vivo human evidence for imaging [¹¹C]ABP688 response to alcohol aligns with preclinical rodent literature¹⁸, suggesting that alcohol-induced glutamate release contributes to the observed decrease in mGluR5 availability. Despite the preliminary nature of the data reported here, it is noteworthy that all subjects exhibited a consistent decrease in [¹¹C]ABP688 binding. This uniformity in response supports the reliability of our findings and underscores the potential of [¹¹C]ABP688 PET imaging to measure alcohol-induced changes in mGluR5 availability, although the results should be validated in larger cohorts. A plausible mechanism for this finding is that increases in glutamate cause mGluR5s to internalize within the cell membrane, and these receptors are no longer available for [¹¹C]ABP688 binding since this radiotracer targets an allosteric site on mGluR5 on cell surface receptors only³⁸. This decrease in [¹¹C]ABP688 BP_ND following acute alcohol highlights potential disruptions in glutamate signaling pathways, which are essential for synaptic plasticity and cognitive functions³⁹. Such disruptions can lead to long-term changes in glutamate function and behavior associated with AUD and subsequent recovery^11,40, and are important areas of research for future studies leveraging this imaging paradigm as is evaluation of targeted therapies aimed at modulating glutamate signaling to treat or prevent AUD.

The primary outcome measure for this study was [¹¹C]ABP688 BP_ND using the cerebellum as a reference region. This allowed for use of the full dataset, as arterial blood sampling was available for both baseline and challenge studies in only 4 participants. The cerebellum contains small but significant [¹¹C]ABP688 specific binding, which could introduce systematic biases and potentially reduce the accuracy of detected associations^41,42. Cerebellum [¹¹C]ABP688 V_T values were carefully examined in the data and no significant changes were found after the acute alcohol, supporting validity of this reference region in the context of this challenge. Should alcohol indeed cause small reductions in cerebellum [¹¹C]ABP688 specific binding, this would cause underestimation of decreases in [¹¹C]ABP688 BP_ND, increasing confidence for using this analytic approach in the context of alcohol challenge. Indeed, [¹¹C]ABP688 BP_ND values derived using the cerebellum correlate well with those obtained from arterial input⁴³, and the inherent variability of [¹¹C]ABP688 V_T values^28,44 are poorer than that of [¹¹C]ABP688 BP_ND³⁵. Future investigations into alcohol's effects on these areas may require larger sample sizes to strengthen statistical confidence in the findings. Taken together, this supports use of [¹¹C]ABP688 BP_ND as the primary outcome for this study, although caution must be used when interpreting study results.

Previous human imaging studies with PET^45–48 and arterial spin labeling^{23–25,49,50} have shown that alcohol stimulates cortical gray matter hemodynamics across varying BALs. In line with these findings, our study observes a modest increase in [¹¹C]ABP688 R₁ values, which represent relative blood flow. This increase in R₁ highlights the vasodilatory effect of acute alcohol consumption. Importantly, a strong positive correlation was found between peak BAL and ΔR₁, particularly in cortical gray matter regions, similar to previous studies^45,46,51. These findings highlight the necessity of accounting for regional blood flow alterations when studying alcohol's impact on the brain, especially in fMRI studies of both resting state and task-based activities, as well as in multimodal (including PET and fMRI) approaches⁵².

In conclusion, this study provides in vivo human evidence that an oral alcohol challenge decreased [¹¹C]ABP688 BP_ND values in cortical and subcortical regions, which may reflect glutamate fluctuations in the brain as previously reported in preclinical studies. These results establish a novel imaging paradigm that allows for the examination of the dynamic effects of acute alcohol on human brain glutamate function and investigate glutamatergic underpinnings of AUD. This study advances the field’s knowledge of the acute effects of alcohol on the brain and the associated glutamate response, providing a foundation for future research in this area.

Acknowledgements

We express our gratitude to the exceptional staff at the Yale PET Center for their expertise and support in radiochemistry, metabolite analysis, and image acquisition. We also extend our thanks to the personnel at the Clinical Neuroscience Research Unit at the Connecticut Mental Health Center and the Hospital Research Unit at the Yale Clinical Center for Investigation for their assistance with participant monitoring and evaluation.

Funding

We gratefully acknowledge the funding support from the National Institute on Alcohol Abuse and Alcoholism (K01AA024788; P50AA012870; K24031345) and State of Connecticut Support for the Clinical Neuroscience Research Unit.

Competing interests

The authors declare they have no competing financial and/or non-financial interests in relation to the work described herein.

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The authors declare no competing interests.

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

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Abstract

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Introduction

Material and methods

Recruitment and Study Participants

Experimental Design

Imaging data acquisition

Preprocessing and Kinetic modeling

Statistical analysis

Results

Participant demographics and characteristics

Using the Cerebellum as a reference region

Acute alcohol decreases brain mGluR5 availability

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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