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Two hundred and fifty‐six consecutive alcoholics admitted for detoxification, but not having delirium tremens, were evaluated for hypertension. Thirty‐three per cent (84) of the alcoholics had a blood pressure ≥ 160/95 mm Hg on or within 72 hr of admission. In 71% (60 of 84) of alcoholics with hypertension, pressure elevation was transitory, whereas 29% (24 of 84) required therapy. After 4 to 5 days of abstinence, alcoholics with transitory hypertension, whose blood pressure was no longer elevated, had a larger increment of pressure (p amp;lt; 0.001) with a cold pressor test than did normotensive alcoholics. Hypertensive alcoholics were older and tended to use greater amounts of alcohol, but their liver enzymes, alcohol levels on admission, and serum magnesium concentrations did not distinguish them from normotensive alcoholics. Basal plasma renin activity and epinephrine were elevated in both hypertensive and normotensive alcoholics, whereas plasma norepinephrine was normal. Although plasma renin activity (4.08 ± 0.9 vs. 2.88 ± 0.4 ng/ml/hr) and epinephrine (138 ± 17 vs. 108 ± 28 pg/ml) were higher in alcoholics with hypertension than in normotensive alcoholics, differences were not significant. However, elevated plasma epinephrine was found in 86% of alcoholics with hypertension, whereas only 44% of normotensive subjects had elevations (x2= 5.49; p = 0.01). Although alcoholics with hypertension demonstrated an exaggerated catecholamine response with the cold pressor test, these changes per se did not explain the elevations in blood pressure. Thus, a transitory, reactive form of hypertension associated with increased catecholamines and vascular hyperresponsiveness is present in alcoholics.

C57BL/6J (C57) and DBA/2J (DBA) mice respond differently to drugs that affect dopamine systems, including alcohol. The current study compared effects of D1 and D2 receptor agonists and antagonists, and the interaction between D1/D2 antagonists and alcohol, on intracranial self-stimulation in male C57 and DBA mice to determine the role of dopamine receptors in the effects of alcohol on brain stimulation reward (BSR). In the initial strain comparison, dose effects on BSR thresholds and maximum operant response rates were determined for the D1 receptor agonist SKF-82958 (±-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.1–0.56 mg/kg) and antagonist SCH 23390 (+-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepinehydrochloride; 0.003–0.056 mg/kg), and the D2 receptor agonist quinpirole (0.1–3.0 mg/kg) and antagonist raclopride (0.01–0.56 mg/kg). For the alcohol interaction, SCH 23390 (0.003 mg/kg) or raclopride (0.03 mg/kg) was given before alcohol (0.6–2.4 g/kg p.o.). D1 antagonism dose-dependently elevated and SKF-82958 dose-dependently lowered BSR threshold in both strains; DBA mice were more sensitive to SKF-82958 effects. D2 antagonism dose-dependently elevated BSR threshold only in C57 mice. Low doses of quinpirole elevated BSR threshold equally in both strains, whereas higher doses of quinpirole lowered BSR threshold only in C57 mice. SCH 23390, but not raclopride, prevented lowering of BSR threshold by alcohol in DBA mice. Conversely, raclopride, but not SCH 23390, prevented alcohol potentiation of BSR in C57 mice. These results extend C57 and DBA strain differences to D1/D2 sensitivity of BSR, and suggest differential involvement of D1 and D2 receptors in the acute rewarding effects of alcohol in these two mouse strains.

The nucleus accumbens (NAc) is a ventral striatal structure underlying reward, reinforcement, and motivation, with extensive anatomic and functional connections to a wide range of affective processing structures (medial prefrontal cortex (mPFC), amygdala, and insula). Characterizing how acute alcohol intake affects resting state functional connectivity (rsFC) between the nucleus accumbens (NAc) and these regions will improve mechanistic understanding of alcohol's neurobehavioral effects, including the neural overlap between acute alcohol effects and pain processing.Fifteen healthy social drinkers (10 women; age: 25-45 years) were included in the study. Participants completed one session in which they consumed an alcohol dose targeting a breath alcohol concentration of 0.08 g/dL, and in a second a placebo beverage. Nine-minute resting state fMRI scans were acquired 30-35 min after beverage administration during each session. rsFC between NAc and a priori corticolimbic regions of interest (mPFC, amgydala, and insula), were compared between beverage conditions. We also conducted an exploratory whole-brain seed-to-voxel analysis of NAc FC.Alcohol intake reduced rsFC between NAc and mPFC, as well as NAc and amygdala. Alcohol also reduced rsFC between NAc and a 97-voxel cluster including bilateral paracingulate cortex and anterior cingulate cortex.Findings suggest that acute alcohol intake reduces rsFC between NAc and several structures, including mPFC, amygdala, and rostral ACC in healthy social drinkers. These structures underlie reward, motivated behavior, and emotion regulation, and may provide mechanistic insight to how alcohol affects related processes, including pain.

Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use.In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine.Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively.These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

Prenatal ethanol exposure produces severe changes in brain, liver, and kidney through mechanisms involving growth factors. These molecules regulate survival, differentiation, maintenance, and connectivity of brain, liver, and kidney cells. Despite the abundant available data on the short and mid-lasting effects of ethanol intoxication, only few data show the long-lasting damage induced by early ethanol administration. The aim of this study was to investigate changes in nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) in brain areas, liver, and kidney of 18-mo-old male mice exposed perinatally to ethanol at 11% vol or to red wine at the same ethanol concentration. The authors found that ethanol per se elevated NGF, BDNF, HGF, and VEGF measured by ELISA in brain limbic system areas. In the liver, early exposure to ethanol solution and red wine depleted BDNF and VEGF concentrations. In the kidney, red wine exposure only decreased VEGF. In conclusion, the present study shows that, in aged mice, early administration of ethanol solution induced long-lasting damage at growth factor levels in frontal cortex, hippocampus, and liver but not in kidney. Otherwise, in mice exposed to red wine, significant changes were observed in the liver and kidney but not in the hippocampus and frontal cortex. The brain differences in ethanol-induced toxicity when ethanol is administered alone or in red wine may be related to compounds with antioxidant properties present in the red wine.

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.

Groups of rats were maintained on a daily regimen of 22 h of water deprivation followed by a 2-h opportunity to take either water or a sweetened ethanol solution (ES). In one experiment, it was shown that previous morphine (M) dependence had no effect on initial daily intakes of fluids. After stable ES intakes were achieved, a variety of pharmacological manipulations were assessed for their effects on intake of the ES. Nalmefene, an opioid antagonist, dose-relatedly decreased intakes of ES, and was effective across days of injections. Fluoxetine (FX), a serotonergic reuptake inhibitor, also reduced ES intakes dose relatedly, and across days of injections, but the reduction was not as great as that seen with opioid antagonists. A small dose of M increased ES intakes when given in combination with an ineffective dose of FX, just as it does by itself. However, M had no effect on ES intakes in combination with an effective dose of FX. Pimozide (PIM), a dopaminergic antagonist, dose-relatedly decreased intakes of ES and water, and responding for positively reinforcing intracranial stimulation (ICS). When given in combination, M blunted PIM's reduction of ES intake, but had no effect on PIM's ability to decrease either intake of water or responding for ICS. Amphetamine did not reliably affect rats' intakes of ES across a range of doses. The data, in addition to previous work, lead to the idea that endogenous opioid systems are more salient, with respect to intake of alcoholic beverages, than the other tested neurotransmitter systems. Furthermore, the collective data suggest that a long-lasting opioid antagonist may be an effective pharmacological adjunct to other treatments for alcohol abuse and alcoholism.

The effects of maternal alcohol consumption on the levels and metabolism of neurotransmitters in offspring are reviewed. In addition, studies of CNS myelination and hepatic lipids are discussed. In utero exposure to ethanol is reported to alter the steady-state levels, metabolism or release of catecholamines, octopamine, serotonin, glutamate, GABA, acetylcholine and histamine. However, with the exception of a deficit of hypothalamic norepinephrine and a deficit of whole brain serotonin, most of the neurotransmitter alterations appear to be either transient or were detected when ethanol was present in the fetus or neonatal animals. There are conflicting reports on the effect of pre- and early postnatal exposure to ethanol on CNS myelination in the rat. However, it appears that if ethanol and control rats were of comparable body weights, there were only minor differences in myelination. Nonetheless, if the rat mothers consumed ethanol for 1 1/2--2 months prior to conception and during gestation, the offspring had increased myelin early in development. An examination of hepatic lipids in the fetal and neonatal rats that were exposed to ethanol in utero and at the time of sacrifice demonstrated an increased concentration of hepatic lipids and decreased fatty acid oxidation. The discussion of the neurotransmitter, myelin and hepatic lipid studies include an assessment of the nutritional status of the animals and the permanence of any observed abnormalities.