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Abstract Aims Alcohol use alters the reward signaling processes contributing to the development of addiction. We studied the effects of alcohol use disorder (AUD) on brain regions and blood of deceased women and men to examine sex-dependent differences in epigenetic changes associated with AUD. We investigated the effects of alcohol use on the gene promoter methylation of GABBR1 coding for GABAB receptor subunit 1 in blood and brain. Methods We chose six brain regions associated with addiction and the reward pathway (nucleus arcuatus, nucleus accumbens, the mamillary bodies, amygdala, hippocampus and anterior temporal cortex) and performed epigenetic profiling of the proximal promoter of the GABBR1 gene of post-mortem brain and blood samples of 17 individuals with AUD pathology (4 female, 13 male) and 31 healthy controls (10 female, 21 male). Results Our results show sex-specific effects of AUD on GABBR1 promoter methylation. Especially, CpG −4 showed significant tissue-independent changes and significantly decreased methylation levels for the AUD group in the amygdala and the mammillary bodies of men. We saw prominent and consistent change in CpG-4 across all investigated tissues. For women, no significant loci were observed. Conclusion We found sex-dependent differences in GABBR1 promoter methylation in relation to AUD. CpG-4 hypomethylation in male individuals with AUD is consistent for most brain regions. Blood shows similar results without reaching significance, potentially serving as a peripheral marker for addiction-associated neuronal adaptations. Further research is needed to discover more contributing factors in the pathological alterations of alcohol addiction to offer sex-specific biomarkers and treatment.

Citalopram, a selective 5-HT uptake inhibitor with antidepressant properties, was assessed in three studies in 12 healthy subjects using a battery of EEG, psychological, subjective and symptomatic measures. Study A involved the administration of citalopram, 20 mg and 40 mg, amitriptyline 50 mg and placebo in single dose using a balanced cross-over design. The test battery was applied before, and 1 and 3 h after each drug. Citalopram decreased slow-wave EEG activity whereas amitriptyline increased power in most EEG wavebands. Citalopram increased tapping rate and symbol copying whereas amitriptyline impaired these and other psychomotor tasks. Subjectively, amitriptyline was much more sedative than citalopram and produced more complaints of dry mouth. Study B comprised the administration of citalopram in the usual clinical dose of 40 mg, amitriptyline in the low clinical dose of 75 mg and placebo, each given for 9 nights using a balanced cross-over design. The test battery was applied on the first morning (pre-drug) and on the morning after the last nightly dose. None of the physiological tests showed any drug effects. Subjectively, citalopram was associated with feelings of shaking, nausea, loss of appetite and physical tiredness; amitriptyline produced feelings of shaking, nausea, loss of appetite, dryness of mouth, irritability, dizziness and indigestion; in general, amitriptyline effects were more marked than those of citalopram. Plasma samples were taken on the last day and plasma concentrations of both drugs and their metabolites were found to be in the expected range for the regimens used.(ABSTRACT TRUNCATED AT 250 WORDS)

The isolated perfused rat brain was used for a comparative study of the effects of chloral hydrate and trichloroethanol on cerebral energy metabolism. After a perfusion period of 30 min the brain levels of the following substrates and metabolites were measured spectrophotometrically: P-creatine, creatine, ATP, ADP, AMP, glycogen, glucose, glucose-6-P, fructose diphosphate, α-glycero-P, dihydroxyacetone-P, pyruvate, lactate, glutamate, α-ketoglutarate and ammonia. Furthermore, the concentration of chloral hydrate and trichloroethanol in the isolated brain and in the perfusion medium was measured colorimetrically. Little more than 10% of chloral hydrate in the isolated brain and in the perfusion medium were reduced to trichloroethanol. In intact animals there were about 70% of chloral hydrate transformed. Chloral hydrate and trichloroethanol caused an accumulation of P-creatine, no change in the lactate/pyruvate ratio, an increase of the glucose concentration and a decrease of glucose-6-P level in the isolated brain. The rise of brain glucose level was more pronounced after trichloroethanol than after chloral hydrate. The effects of chloral hydrate and trichloroethanol on brain glucose and glucose-6-P levels suggest an inhibition of brain hexokinase activity by these drugs.

In the immature mammalian brain during a period of rapid growth (brain growth spurt/synaptogenesis period), neuronal apoptosis can be triggered by the transient blockade of glutamate N-methyl-d-aspartate (NMDA) receptors, or the excessive activation of gamma-aminobutyric acid (GABA(A)) receptors. Apoptogenic agents include anesthetics (ketamine, nitrous oxide, isoflurane, propofol, halothane), anticonvulsants (benzodiazepines, barbiturates), and drugs of abuse (phencyclidine, ketamine, ethanol). In humans, the brain growth spurt period starts in the sixth month of pregnancy and extends to the third year after birth. Ethanol, which has both NMDA antagonist and GABA(A) agonist properties, is particularly effective in triggering widespread apoptotic neurodegeneration during this vulnerable period. Thus, maternal ingestion of ethanol during the third trimester of pregnancy can readily explain the dysmorphogenic changes in the fetal brain and consequent neurobehavioral disturbances that characterize the human fetal alcohol syndrome. In addition, there is basis for concern that agents used in pediatric and obstetrical medicine for purposes of sedation, anesthesia, and seizure management may cause apoptotic neuronal death in the developing human brain.

Stress and alcohol cues trigger alcohol consumption and relapse in alcohol use disorder. However, the neurobiological processes underlying their interaction are not well understood. Thus, we conducted a randomized, controlled neuroimaging study to investigate the effects of psychosocial stress on neural cue reactivity and addictive behaviors.Neural alcohol cue reactivity was assessed in 91 individuals with alcohol use disorder using a validated functional magnetic resonance imaging (fMRI) task. Activation patterns were measured twice, at baseline and during a second fMRI session, prior to which participants were assigned to psychosocial stress (experimental condition) or a matched control condition or physical exercise (control conditions). Together with fMRI data, alcohol craving and cortisol levels were assessed, and alcohol use data were collected during a 12-month follow-up. Analyses tested the effects of psychosocial stress on neural cue reactivity and associations with cortisol levels, craving, and alcohol use.Compared with both control conditions, psychosocial stress elicited higher alcohol cue-induced activation in the left anterior insula (familywise error-corrected p < .05) and a stress- and cue-specific dynamic increase in insula activation over time (F22,968 = 2.143, p = .007), which was predicted by higher cortisol levels during the experimental intervention (r = 0.310, false discovery rate-corrected p = .016). Cue-induced insula activation was positively correlated with alcohol craving during fMRI (r = 0.262, false discovery rate-corrected p = .032) and alcohol use during follow-up (r = 0.218, false discovery rate-corrected p = .046).Results indicate a stress-induced sensitization of cue-induced activation in the left insula as a neurobiological correlate of the effects of psychosocial stress on alcohol craving and alcohol use in alcohol use disorder, which likely reflects changes in salience attribution and goal-directed behavior.

The effects of acute, low-dose administration of ethanol (1 g/kg bodyweight) and the mu-opioid receptor agonist etonitazene (30 microg/kg bodyweight) on the activities of the iodothyronine deiodinase isoenzymes were investigated in nine regions of the rat brain. The experiments were performed at three different times of the 24-h cycle (1300, 2100 and 0500 hours) and the rats were decapitated 30 and 120 min after administration of the respective drugs. Interest was focused on changes in the two enzymes that catalyze 1) 5'-deiodination of thyroxine (T4) to the biologically active triiodothyronine (T3), i.e. type II 5'-deiodinase (5'D-II) and 2) 5 (or inner-ring) deiodination of T3 to the biologically inactive 3'3-T2, i.e. type III deiodinase (5D-III). 120 min after administration of ethanol and etonitazene 5D-III activity was selectively inhibited in the frontal cortex (at 1300 and 1700 hours) and the amygdala (at all three measuring times). The 5'D-II activity was significantly enhanced 30 min after administration of etonitazene in the frontal cortex, amygdala and limbic forebrain, and after administration of ethanol in the amygdala alone. These effects on 5'D-II activity were seen at 2100 hours only. In conclusion, the two different addictive drugs both reduced the inactivation of the physiologically active thyroid hormone T3 and enhanced its production. These effects occurred almost exclusively in the brain regions which were most likely to be involved in the rewarding properties of addictive drugs. As thyroid hormones have stimulating and mood-elevating properties, an involvement of these hormones in the reinforcing effects of addictive drugs seems conceivable.

Night time alcohol ingestion influences nocturnal breathing in patients with sleep apnea syndrome or respiratory diseases. To evaluate the influence of nocturnal alcohol ingestion on the cardio-respiratory activity of healthy men, 8 snoring and 13 non-snoring male subjects were measured for 3 nights after alcohol ingestion. Blood alcohol concentration was 0.0, 0.5 and 0.8%, respectively. During each night polysomnographic data were obtained and analyzed. The apnea-hypopnea index was significantly higher in snoring than in non-snoring participants and increased in both groups under the influence of alcohol. Non-snoring males showed a significant increase of hypopneas under nocturnal alcohol ingestion (0.96-1.65-2.06). Mean oxygen saturation (SAO(2)) was significantly higher in non-snoring compared to snoring males, and both groups showed a significant decrease (non-snoring: 96.06%-95.7%-95.52%; snoring: 95.54%-94.74%-94.53%). Snoring individuals had a significant decrease in SAO(2) during NREM4, whereas SAO(2) was reduced significantly in REM and NREM3 in non-snoring subjects. The nocturnal heart rate was significantly increased in both groups under the influence of alcohol. The study proves that snoring and non-snoring healthy males are affected by nocturnal alcohol ingestion. Under the effect of alcohol, these patients can develop signs of a sleep apnea syndrome, which should be considered clinically.

Both the antiepileptic drug valproic acid (VPA) and ethanol interfere with fetal folate metabolism, which may contribute to their mechanism of teratogenesis. Therefore, the possible interaction between VPA and ethanol was investigated in mice. Ethanol (2 x 2.5 g/kg) was given orally 4 and 1 h prior to VPA (300 and 400 mg/kg, SC) in day 8.25 pregnant NMRI mice. Fetuses were examined for exencephaly, embryolethality, and fetal weight retardation on day 18 of gestation. Higher doses of ethanol (2 x 5 g/kg, orally) at day 7.5 and 8 of gestation resulted in 22% embryolethality and 1.7% exencephaly with no effect on fetal weight. Ethanol, however, increased VPA (400 mg/kg, SC)-induced exencephaly, embryolethality, and fetal weight retardation. It also increased VPA (300 mg/kg, SC)-induced exencephaly without affecting embryotoxicity. A minimum of two oral doses of 2.5 g/kg ethanol, 1 and 4 h, or 1 and 6 h prior to VPA administration were needed to produce maximum potentiation of the effects observed. These ethanol doses increased plasma VPA levels of day 8.25 pregnant mice given 400 mg/kg VPA to values comparable to the levels of mice given only VPA at a higher dose level (500 mg/kg). The incidence of exencephaly was increased from 35% for VPA (400 mg/kg) to 59% when VPA was given with ethanol. This incidence was similar to that of 60% for the high dose of VPA (500 mg/kg) administered without ethanol. Maternal plasma ethanol concentration peaked at 193, 196, and 183 mg/dL 15, 30, and 60 min, respectively, after oral ethanol administration (2.5 g/kg), and fell to 110 mg/dL by 2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

SUMMARY Depth of anaesthesia and tendency to sleep were assessed by means of electroencephalography in healthy volunteers following the administration of different intravenous anaesthetics. Graphs of sleep depth were constructed from the records. Characteristic differences were observed in the postanaesthetic course between methohexitone, thiobarbiturates, neuroleptanalgesics, and propanidid. Whereas the effects of propanidid rapidly diminished, this was not the case with the other drugs, and even after 12 hours the potentiating effect of a small quantity of alcohol was discernible after methohexitone, thiopentone and thiobutobarbitone. The results suggest that after intravenous barbiturate anaesthesia for out-patient procedures the patient should be cautioned against driving or drinking alcohol for 24 hours, but after propanidid a 2-hour period is sufficient.