The purpose of this study is to learn how drinking alcohol affects how people experience stress and how that is affected by the body's chemistry. Specifically, the investigators will be studying relationships of drinking and a stress hormone called cortisol. The investigators believe that results will lead us to find more effective ways to help people stop or reduce drinking when participants are drinking at harmful levels.
Brain acetate consumption will be measured with a novel method called Deuterium Metabolic Imaging (DMI), in which sodium acetate that has been labeled with deuterium, a non-radioactive isotope of hydrogen, is administered intravenously over two hours, while Magnetic Resonance Spectroscopy (MRS) is used to map the appearance of the deuterium in glutamate and glutamine regionally through the brain. That combination of glutamate and glutamine, called Glx, serves as a tag to measure the brain's rate of acetate consumption. That is, the more deuterium appears in Glx, the more acetate that part of the brain consumes. In the same people, investigators will perform structural Magnetic Resonance Imaging (MRI) for co-registration with the MRI and assess regional brain volumes. Investigators will also obtain measures of drinking and stress, and will measure participants serum cortisol levels and rates of cortisol turnover. Each set of measures will be compared across groups, and the measurements of acetate uptake will be compared with all other measures for associations.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
50
Deuterium Metabolic Imaging (DMI) is a method by which Magnetic Resonance Spectroscopy (MRS) is used to map the appearance of deuterium from a tracer source (e.g., deuterated acetate) in products of metabolism. In this case we will map the combination of glutamate and glutamine, called Glx, to serve as a tag to measure the brain's rate of acetate consumption. That is, the more deuterium appears in Glx, the more acetate that part of the brain consumes.
The Anlyan Center, 300 Cedar St.
New Haven, Connecticut, United States
RECRUITINGYale University
New Haven, Connecticut, United States
NOT_YET_RECRUITINGRate of Conversion of Acetate to Glutamate + Glutamine (Glx) in the Brain
DMI data will be acquired during infusions of 2H-labeled Ac, using a 4-Tesla magnet. Deuterium flow from \[2,2,2-2H3\]Ac to glutamate (Glu) and glutamine (Gln). Ac forms AcetylCoA at a rate CMRAc and is oxidized by astroglia (VtcaA), labeling the small glial Glu pool (5-10% of the total Glu110).Astroglial Glu is converted to Gln and sent to neurons (Vcycle), where it is converted to labeled Glu. It mixes with the large neuronal Glu pool, fed also by unlabeled carbon mostly from glucose via neuronal oxidation (VtcaN), and the diluted Glu is released and taken up by glia for reconversion to Gln. With 2H, the sum of Glu and Gln is detected as \[2H\]Glx. The faster the rate of acetate consumption, the faster the appearance of \[2H\]Glx.
Time frame: Baseline and for TS, once within approximately one week and again at approximately one month
Concentration of [2H]Glx in the brain during administration of [2H]acetate
DMI data will be acquired during infusions of 2H-labeled Ac, using a 4-Tesla magnet. Deuterium flow from \[2,2,2-2H3\]Ac to glutamate (Glu) and glutamine (Gln). Ac forms AcetylCoA at a rate CMRAc and is oxidized by astroglia (VtcaA), labeling the small glial Glu pool (5-10% of the total Glu110).Astroglial Glu is converted to Gln and sent to neurons (Vcycle), where it is converted to labeled Glu. It mixes with the large neuronal Glu pool, fed also by unlabeled carbon mostly from glucose via neuronal oxidation (VtcaN), and the diluted Glu is released and taken up by glia for reconversion to Gln. With 2H, the sum of Glu and Gln is detected as \[2H\]Glx. The faster the rate of acetate consumption, the faster the appearance of \[2H\]Glx.
Time frame: Baseline and for treatment seekers, once after 1 month sober.
Rate of Cortisol Turnover
Plasma cortisol concentrations and enrichments will be measured in the Chemical Metabolism Core directed by Dr. Kibbey. Crashed plasma samples will be applied to a Phenomenex Kinetex F5 Core-shell LC column (100 x 2.1 mm, 2.6 µm), with 0.3 mL/min linear gradients from 100% aqueous phase (95% water, 5% acetonitrile and 0.1% formic acid) to 100% organic phase (95% acetonitrile, 5% water and 0.1% formic acid) in 20 min. Cortisol ions are measured in both positive and negative MS modes the Sciex TripleTOF 6600 using an information-dependent analysis (IDA) workflow consisting of a TOF MS scan (200 msec) and a high-resolution IDA experiment (70 msec each) monitoring 10 candidate ions per cycle. The ion source conditions are as follows; Ion spray voltage = 5000 V for positive mode and -4500V for negative mode, ion source gas 1 (GS1) = 50, ion source gas 2 (GS2) = 50, curtain gas (CUR) = 30, temperature (TEM) = 400 oC.
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Time frame: Baseline and for treatment seekers, once after 1 month sober.