Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice.

RATIONALE: After alcohol ingestion, the brain partly switches from consumption of glucose to consumption of the alcohol metabolite acetate. In heavy drinkers, the switch persists after abrupt abstinence, leading to the hypothesis that the resting brain may be "starved" when acetate levels suddenly drop during abstinence, despite normal blood glucose, contributing to withdrawal symptoms. We hypothesized that ketone bodies, like acetate, could act as alternative fuels in the brain and alleviate withdrawal symptoms. OBJECTIVES: We previously reported that a ketogenic diet during alcohol exposure reduced acute withdrawal symptoms in rats. Here, our goals were to test whether (1) we could reproduce our findings, in mice and with longer alcohol exposure; (2) ketone bodies alone are sufficient to reduce withdrawal symptoms (clarifying mechanism); (3) introduction of ketogenic diets at abstinence (a clinically more practical implementation) would also be effective. METHODS: Male C57BL/6NTac mice had intermittent alcohol exposure for 3 weeks using liquid diet. Somatic alcohol withdrawal symptoms were measured as handling-induced convulsions; anxiety-like behavior was measured using the light-dark transition test. We tested a ketogenic diet, and a ketone monoester supplement with a regular carbohydrate-containing diet. RESULTS: The regular diet with ketone monoester was sufficient to reduce handling-induced convulsions and anxiety-like behaviors in early withdrawal. Only the ketone monoester reduced handling-induced convulsions when given during abstinence, consistent with faster elevation of blood ketones, relative to ketogenic diet. CONCLUSIONS: These findings support the potential utility of therapeutic ketosis as an adjunctive treatment in early detoxification in alcohol-dependent patients seeking to become abstinent. TRIAL REGISTRATION: clinicaltrials.gov NCT03878225, NCT03255031.

Selective proton-observed, carbon-edited (selPOCE) MRS method for measurement of glutamate and glutamine 13 C-labeling in the human frontal cortex.

PURPOSE: 13 C magnetic resonance spectroscopy (MRS) in combination with infusion of 13 C-labeled substrates has led to unique insights into human brain metabolism and neurotransmitter cycling. However, the low sensitivity of direct 13 C MRS and high radiofrequency power requirements has limited 13 C MRS studies to predominantly data acquisition in large volumes of the occipital cortex. The purpose of this study is to develop an MRS technique for localized detection of 13 C-labeling of glutamate and glutamine in the human frontal lobe. METHODS: We used an indirect (1 H-[13 C]), proton-observed, carbon-edited MRS sequence (selPOCE) for detection of 13 C-labeled metabolites in relatively small volumes located in the frontal lobe at 4 T. The SelPOCE method allows for selective and separate detection of glutamate and glutamine resonances, which significantly overlap at magnetic field strengths used for clinical MRI. RESULTS: Phantom data illustrate how selPOCE can be tuned to selectively detect 13 C labeling in different metabolites. Three-dimensional specific absorption rate simulations of radiofrequency power deposition show that the selPOCE method operates comfortably within the global and local Food and Drug Administration specific absorption rate guidelines. In vivo selPOCE data are presented, which were acquired from a 45-mL volume in the frontal lobe of healthy subjects. The in vivo data show the time-dependent 13 C-labeling of glutamate and glutamine during intravenous infusion of [1-13 C]-glucose. Metrics describing spectral fitting quality of the glutamate and glutamine resonances are reported. CONCLUSIONS: The SelPOCE sequence allows the detection of 13 C-labeling in glutamate and glutamine from a relatively small volume in the human frontal lobe at low radiofrequency power requirements. Magn Reson Med 80:11-20, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Neuroimaging insights into the role of cortical GABA systems and the influence of nicotine on the recovery from alcohol dependence.

This paper reviews evidence suggesting that nicotine and tobacco smoke profoundly modulate the effects of alcohol on γ-aminobutyric acid (GABA) neuronal function, specifically at the GABA(A)-benzodiazepine receptor (GABA(A)-BZR). The focus of this paper is on recent neuroimaging evidence in preclinical models as well as clinical experiments. First, we review findings implicating the role of alcohol at the GABA(A)-BZR and discuss the changes in GABA(A)-BZR availability during acute and prolonged alcohol withdrawal. Second, we discuss preclinical evidence that suggests nicotine affects GABA neuronal function indirectly by a primary action at neuronal nicotinic acetylcholine receptors. Third, we show how this evidence converges in studies that examine GABA levels and GABA(A)-BZRs in alcohol-dependent smokers and nonsmokers, suggesting that tobacco smoking attenuates the chemical changes that occur during alcohol withdrawal. Based on a comprehensive review of literature, we hypothesize that tobacco smoking minimizes the changes in GABA levels that typically occur during the acute cycles of drinking in alcohol-dependent individuals. Thus, during alcohol withdrawal, the continued tobacco smoking decreases the severity of the withdrawal-related changes in GABA chemistry. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Regional cerebral blood flow and magnetic resonance spectroscopic imaging findings in diaschisis from stroke.

BACKGROUND AND PURPOSE: This study evaluated blood flow and metabolite changes in cerebral diaschisis from internal capsule region infarction using regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) and 1H magnetic resonance spectroscopic imaging (MRSI). We hypothesized that complementary measures of diaschisis effects in white matter (characterized by 1H MRSI) and gray matter (characterized by changes in rCBF) can be measured and exhibit parallel changes. METHODS: Five stroke patients and 16 normal controls underwent Tc-99m hexamethylpropyleneamine-oxime brain SPECT and 1H MRSI at 4.1 T. The metabolites N-acetyl aspartate (NAA) and creatine (Cr) were measured using 1H MRSI. The tissue content was expressed as the percent of gray or white matter in each MRSI voxel to allow comparison of the differential effects of diaschisis in gray and white matter tissue types. The blood flow and metabolite changes were evaluated at superior cerebral regions distant from the stroke to allow a measure of diaschisis relatively unconfounded by their expected changes in the infarction region. RESULTS: The rCBF SPECT data in stroke patients showed a perfusion defect, with size ranging from 1.23 cc to 10.23 cc, in the region of cortical diaschisis. 1H MRSI showed increased Cr/NAA ratios in regions of white matter diaschisis. There was a tendency for larger rCBF defect size to be associated with greater increases in Cr/NAA values in the same diaschitic cerebral hemisphere, ipsilateral to the infarction. CONCLUSION: Diaschisis ipsilateral to stroke in white matter can be characterized by 1H MRSI, and diaschisis ipsilateral to stroke in cortical gray matter regions can be characterized by changes in rCBF. The tendency for greater reductions in cortical rCBF values to be associated with increased Cr/NAA values in the same diaschitic cerebral hemisphere implies that a relationship exists between rCBF reductions in gray matter and abnormal changes in white matter subservient to it.