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Abstract— Chronic ethanol ingestion in rats leads to a slow rise in brain alcohol dehydrogenase activity which levels off after 2 weeks at approximately twice the initial activity. The half‐time of the rise is approximately 8 days. Abrupt withdrawal of the ethanol is followed by a rapid decline of the brain alcohol dehydrogenase activity to the normal level with a half‐time of approximately 15 h. The difference in time constants between the rise in enzyme activity during ethanol‐feeding and its decline following withdrawal suggests that the increased enzyme activity is at least in part the result of a reduced rate constant of enzyme degradation in the presence of ethanol. The effect of ethanol on brain alcohol dehydrogenase activity is not altered by supplementation of the diet with carbohydrate or vitamins. The effect is seen only in the cerebral hemispheres and not in the brain‐stem. Acquisition of tolerance to ethanol during chronic ethanol ingestion and its extinction following withdrawal follow almost the same time courses as the changes in brain alcohol dehydrogenase activity.

Background:Hyperreactivity and impaired sensory gating of the acoustic startle response in alcohol dependence has been suggested to reflect a residual effect of previous detoxifications, increasing the severity of subsequent withdrawal episodes. Previous studies on the acoustic startle only included early‐onset alcohol‐dependent patients. The observed abnormalities may therefore also be specific for this subtype of alcohol dependence. We investigated the acoustic startle response in alcohol‐dependent patients and healthy controls and hypothesized that (i) early‐onset alcohol‐dependent patients show increased acoustic startle responses compared with late‐onset alcohol‐dependent patients and healthy controls, and (ii) the duration of alcohol dependence or the number of prior detoxifications would not explain the differences in the acoustic startle between early‐ and late‐onset alcohol dependence.Methods:The acoustic startle reflex was assessed in detoxified, male alcohol‐dependent patients (N = 83) and age‐matched healthy male controls (N = 86). Reflex eye blink responses to an auditory startle stimulus were measured by means of electromyographic recordings over the right orbicularis oculi muscle. Reflex amplitudes and levels of prepulse inhibition (PPI) were analyzed.Results:There was no association between number of previous withdrawals and the startle response or PPI. Early‐onset alcohol‐dependent patients showed higher acoustic startle amplitudes compared with late‐onset alcohol‐dependent patients and healthy controls [75/105 dB: F(2, 166) = 9.2, p < 0.001; 85/105 dB: F(2, 166) = 12.1, p < 0.001; 95 dB: F(2, 166) = 8.2, p < 0.001; 105 dB: F(2, 166) = 9.7, p < 0.001], and there were no differences in PPI.Conclusions:Increased acoustic startle response in detoxified early‐onset alcohol‐dependent patients may reflect a trait marker specifically involved in early‐onset alcohol dependence. The findings of the current study do not support the hypothesis that the increased startle response is a residual state marker.

During MR-guided high-intensity focused ultrasound (HIFU) therapy, ultrasound absorption in the near field represents a safety risk and limits efficient energy deposition at the target. In this study, we investigated the feasibility of using T2 mapping to monitor the temperature change in subcutaneous adipose tissue layers.The T2 temperature dependence and reversibility was determined for fresh adipose porcine samples. The accuracy was evaluated by comparing T2 -based temperature measurements with probe readings in an ex vivo HIFU experiment. The in vivo feasibility of T2 -based thermometry was studied during HIFU ablations in the liver in pigs and of uterine fibroids in human patients.T2 changed linearly and reversibly with temperature with an average coefficient of 5.2 ± 0.1 ms/°C. For the ex vivo HIFU experiment, the difference between the T2 -based temperature change and the probe temperature was <0.9°C. All in vivo experiments showed temperature-related T2 changes in the near field directly after sonications. As expected, considerable intersubject variations in the cooling times were measured in the in vivo porcine experiments.The reversibility and linearity of the T2 -temperature dependence of adipose tissue allows for the monitoring of the temperature in the subcutaneous adipose tissue layers.

Bruxism is a controversial phenomenon. Both its definition and the diagnostic procedure contribute to the fact that the literature about the aetiology of this disorder is difficult to interpret. There is, however, consensus about the multifactorial nature of the aetiology. Besides peripheral (morphological) factors, central (pathophysiological and psychological) factors can be distinguished. In the past, morphological factors, like occlusal discrepancies and the anatomy of the bony structures of the orofacial region, have been considered the main causative factors for bruxism. Nowadays, these factors play only a small role, if any. Recent focus is more on the pathophysiological factors. For example, bruxism has been suggested to be part of a sleep arousal response. In addition, bruxism appears to be modulated by various neurotransmitters in the central nervous system. More specifically, disturbances in the central dopaminergic system have been linked to bruxism. Further, factors like smoking, alcohol, drugs, diseases and trauma may be involved in the bruxism aetiology. Psychological factors like stress and personality are frequently mentioned in relation to bruxism as well. However, research to these factors comes to equivocal results and needs further attention. Taken all evidence together, bruxism appears to be mainly regulated centrally, not peripherally.

The pharmacokinetic and pharmacodynamic interactions between midazolam and ethanol were studied in the rat in vivo. Ethanol was given as a constant rate intravenous infusion (1.85 mg/min). The pharmacokinetics and pharmacodynamics of midazolam were determined following an intravenous dose of 5 mg/kg in 15 minutes. Amplitudes in the 11.5-30 Hz (beta) frequency band of the EEG was used as a measure of the pharmacological effect. Ethanol infusion resulted in a constant plasma alcohol concentration of 0.44 +/- 0.04 g/l (Mean +/- SE) and had no effect on the baseline value of the EEG effect parameter. Also the pharmacokinetics of midazolam were unchanged. However, a significant parallel shift of the midazolam concentration-EEG effect relationship to lower concentrations was observed. These findings show that there is a pharmacodynamic interaction between midazolam and ethanol in vivo.

In general, Japanese and Caucasians differ in their response to alcohol. To investigate these differences the alcohol clamping method can be used. This strictly controlled infusion regimen provides a reliable tool to study contrasts in central nervous system (CNS) effects and/or alcohol disposition. In this study, twelve Japanese and twelve Caucasian healthy volunteers received two concentrations of intravenous alcohol or placebo using the alcohol clamp. Infusion rates during the steady state phase were used to compare alcohol clearance between the subgroups. Central nervous system (CNS) effects were frequently measured throughout the clamp. On average, significantly lower amounts of alcohol were needed to maintain similar stable concentrations in the Japanese group. However, these differences disappeared when values were corrected for lean body mass. The most pronounced pharmacodynamic differences between the groups were observed on body sway and on the visual analogue scale for subjective alcohol effects, mainly at the highest dose level. The alcohol clamp seems a useful method to compare differences in alcohol metabolism between groups. Some CNS effects of alcohol differed clearly between Japanese and Caucasians, but others did not, even though alcohol levels were stable and similar between the two groups.

AbstractCreatine kinases are important in maintaining cellular‐energy homeostasis, and neuroprotective effects have been attributed to the administration of creatine and creatine‐like compounds. Herein we examine whether ablation of the cytosolic brain‐type creatine kinase (B‐CK) in mice has detrimental effects on brain development, physiological integrity or task performance. Mice deficient in B‐CK (B‐CK–/–) showed no gross abnormalities in brain anatomy or mitochondrial ultrastructure, but had a larger intra‐ and infrapyramidal mossy fibre area. Nuclear magnetic resonance spectroscopy revealed that adenosine triphosphate (ATP) and phosphocreatine (PCr) levels were unaffected, but demonstrated an apparent reduction of the PCr ⇆ ATP phosphorus exchange capacity in these mice. When assessing behavioural characteristics B‐CK–/– animals showed diminished open‐field habituation. In the water maze, adult B‐CK–/– mice were slower to learn, but acquired the spatial task. This task performance deficit persisted in 24‐month‐old, aged B‐CK–/– mice, on top of the age‐related memory decline normally seen in old animals. Finally, a delayed development of pentylenetetrazole‐induced seizures (creating a high‐energy demand) was observed in B‐CK–/– mice. It is suggested that the persistent expression of the mitochondrial isoform ubiquitous mitochondrial CK (UbCKmit) in the creatine/phospho‐creatine shuttle provides compensation for the loss of B‐CK in the brain. Our studies indicate a role for the creatine–phosphocreatine/CK circuit in the formation or maintenance of hippocampal mossy fibre connections, and processes that involve habituation, spatial learning and seizure susceptibility. However, for fuelling of basic physiological activities the role of B‐CK can be compensated for by other systems in the versatile and robust metabolic‐energy network of the brain.

We examined the effects of ethanol ingestion to rats on levels of the beta-carboline norharman in plasma, brain and liver at the end of ethanol ingestion and 10 h after withdrawal. We also investigated the effect of exogenously administered norharman on the behavioural signs of alcohol withdrawal. Ethanol was given by a liquid diet for 21 days. Norharman plasma levels in alcohol fed rats were significantly elevated compared to both control rats and to rats 10 h after withdrawal. Norharman levels in brains and livers showed a similar pattern. The capacity of the livers of both alcohol-dependent and withdrawal rats to catabolise norharman was significantly reduced compared to control rats. Norharman injected intraperitoneally (6.3 mg/kg) attenuated the behavioural signs of alcohol withdrawal significantly. The mechanism behind the increased norharman levels in alcohol-dependent rats may be inhibition of the synthesis and/or activity of liver enzyme(s) responsible for the breakdown of norharman.