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Patients with pure autonomic failure (PAF) and multiple system atrophy (MSA) may complain of feeling light-headed after alcohol ingestion particularly on assumption of the upright posture. The reasons for this have not been investigated. We therefore studied the effects of oral alcohol (40% vodka in sugar-free orange juice) and placebo (juice only) on the systemic and regional (including superior mesenteric artery, SMA) blood flow in nine patients with PAF and six patients with MSA. After alcohol, there was a fall in supine blood pressure (BP) and vasodilatation in the SMA but no change in cardiac output, or forearm muscle and cutaneous blood flow in either PAF or MSA; BP fell further during head-up tilt with no changes in levels of plasma catecholamines. After placebo, there were no changes while supine. We conclude that alcohol lowers supine BP and dilates the SMA with no change in muscle or cutaneous blood flow. Alcohol also enhances the fall in BP during head-up tilt. This may explain the symptoms experienced by PAF and MSA patients after alcohol.

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.

AbstractActivation of potassium (K+) currents plays a critical role in the control of programmed cell death. Because pituitary adenylate cyclase‐activating polypeptide (PACAP) has been shown to inhibit the apoptotic cascade in the cerebellar cortex during development, we have investigated the effect of PACAP on K+ currents in cultured cerebellar granule cells using the patch‐clamp technique in the whole‐cell configuration. Two types of outward K+ currents, a transient K+ current (IA) and a delayed rectifier K+ current (IK) were characterized using two different voltage protocols and specific inhibitors of K+ channels. Application of PACAP induced a reversible reduction of the IK amplitude, but did not affect IA, while the PACAP‐related peptide vasoactive intestinal polypeptide had no effect on either types of K+ currents. Repeated applications of PACAP induced gradual attenuation of the electrophysiological response. In the presence of guanosine 5′‐[γthio]triphosphate (GTPγS), PACAP provoked a marked and irreversible IK depression, whereas cell dialysis with guanosine 5′‐[βthio]diphosphate GDPβS totally abolished the effect of PACAP. Pre‐treatment of the cells with pertussis toxin did not modify the effect of PACAP on IK. In contrast, cholera toxin suppressed the PACAP‐induced inhibition of IK. Exposure of granule cells to dibutyryl cyclic adenosine monophosphate (dbcAMP) mimicked the inhibitory effect of PACAP on IK. Addition of the specific protein kinase A inhibitor H89 in the patch pipette solution prevented the reduction of IK induced by both PACAP and dbcAMP. PACAP provoked a sustained increase of the resting membrane potential in cerebellar granule cells cultured either in high or low KCl‐containing medium, and this long‐term depolarizing effect of PACAP was mimicked by the IK specific blocker tetraethylammonium chloride (TEA). In addition, pre‐incubation of granule cells with TEA suppressed the effect of PACAP on resting membrane potential. TEA mimicked the neuroprotective effect of PACAP against ethanol‐induced apoptotic cell death, and the increase of caspase‐3 activity observed after exposure of granule cells to ethanol was also significantly inhibited by TEA. Taken together, the present results demonstrate that, in rat cerebellar granule cells, PACAP reduces the delayed outward rectifier K+ current by activating a type 1 PACAP (PAC1) receptor coupled to the adenylyl cyclase/protein kinase A pathway through a cholera toxin‐sensitive Gs protein. Our data also show that PACAP and TEA induce long‐term depolarization of the resting membrane potential, promote cell survival and inhibit caspase‐3 activity, suggesting that PACAP‐evoked inhibition of IK contributes to the anti‐apoptotic effect of the peptide on cerebellar granule cells.

Alcoholism and alcohol abuse represent a significant medical and societal problem, and have been thoroughly investigated in humans as well as using animal models. A less well understood aspect of alcohol related disorders is the possible effect of this drug on offspring whose parents were exposed prior to conception. The zebrafish has been successfully employed in alcohol research, however, the effect of exposing the parents to alcohol before fertilization of the eggs on offspring has not been demonstrated in this species. In this proof of concept study, we attempt to address this hiatus. We exposed both adult male and female zebrafish to 0.0% (control) or 0.5% (vol/vol) alcohol chronically for 7 days, subsequently bred the fish within their respective treatment group, collected the fertilized eggs, allowed them to develop, and tested the behavior of free-swimming offspring at their age of 7-9 days post-fertilization. We conducted the analysis in two genetically distinct quasi-inbred strains of zebrafish, AB and TL. Although gross morphology and general activity of the fish appeared unaffected, we found significant behavioral alterations in offspring of alcohol exposed parents compared to offspring of control parents in both strains. These alterations included robustly increased duration and reduced frequency of immobility, increased turn angle, and increased intra-individual variance of turn angle in offspring of alcohol exposed parents in both strains. The mechanisms underlying these behavioral effects or whether the effects are due to exposure of the father, the mother, or both to alcohol are unknown. Nevertheless, our results now set the stage for future studies with zebrafish that will address these questions.

When rats are presented with a novel saccharin solution and immediately injected with either morphine or ethanol, they subsequently develop a conditioned taste aversion (CTA) to the saccharin solution which reflects the aversive component of the conditioning drug. The present study provides evidence which suggests that both morphine-induced and ethanol-induced CTAs can be blocked by the specific high-affinity binding opiate antagonist, naloxazone.

Three drinks containing 0 g (no alcohol, NA), 8 g (low alcohol, LA) and 24 g (high alcohol, HA) of alcohol were formulated which were found to be indistinguishable from one another in sip-and-swallow triangle tests. In a second study, conducted according to a within-subjects design, 14 healthy human volunteers consumed these drinks as part of a small lunchtime meal, in counterbalanced order on 3 different days. They also completed a battery of cognitive tasks, together with mood ratings, before lunch and during the 4 h following lunch. Compared with NA, LA (approximately 0.12 g/kg) significantly increased hit rate on a difficult rapid information processing vigilance task. In contrast, HA (approximately 0.35 g/kg) tended to impair performance of this task. There were no reliable effects of alcohol on performance on less demanding tasks. The low dose of alcohol also improved mood (for example, it significantly reduced tension and uncertainty), suggesting that the improvement in task performance was mediated by the calming or sedative effects of the alcohol. Volunteers did detect alcohol in the HA, but not the LA drink, when they consumed the full drink, confirming the difficulty of disguising the administration of alcohol.

The aggregation of gel-filtered human platelets induced by A23187 is very sensitive to inhibition by ethanol. Similarly when platelets preloaded with [3H]5-hydroxytryptamine ([3H]5HT) are studied in a superfusion system under conditions where aggregation is likely (high platelet density, presence of Ca2+) the rate of release of [3H]5HT induced by A23187 is reduced by the presence of ethanol. However when platelet aggregation is less likely (low platelet density, absence of Ca2+) ethanol does not reduce the rate of [3H]5HT efflux induced by A23187 in superfused platelets. In addition, in contrast to the effects of ethanol on platelet aggregation, the transformation of human red cells to echinocytes induced by A23187 is accelerated by the presence of ethanol. Similarly the increased efflux of 3H from superfused rat striatal slices preloaded with [3H]dopamine which is produced by A23187 is potentiated by ethanol. It is concluded that the inhibitory effect of ethanol on the action of A23187 may be confined to platelet aggregation. This may be because the mechanisms of action of either A23187 or ethanol on platelet aggregation differ from those on other cell functions.

Inositol monophosphatase can be modified at two sites by pyrene maleimide. These sites have been identified as Cys141 and Cys218. Stoichiometric addition of pyrene maleimide allows the sole modification of Cys218. The fluorescence of the pyrene moiety on the modified protein can be excited directly or by resonance energy transfer. The fluorescence properties of the pyrene group on Cys218 allows the interaction of ligands with the enzyme to be monitored. This feature has allowed dissociation constants for various metal ions to be determined and allowed the formation of various enzyme/ligand complexes to be observed. These studies have demonstrated that Mg2+ is required to support Pi binding and that Li+ interacts with a post‐catalytic complex which is only formed in the forward reaction.

Rats of two different ages (2 and 7 months) were treated with an ethanol-containing liquid diet for 24 days and change of the ceramide composition of gangliosides were studied in the brain synaptosomal, microsomal and myelin fractions. Greater differences were observed in the younger age, where ethanol treatment caused a significant increase of C20:1 LCB in GM1 ganglioside of synaptosomes and microsomes and in GD1a of myelin.