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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.

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.

Young and aged rats were treated chronically with ethanol or scopolamine. Muscarinic receptors were measured in cerebral cortex, hippocampus and striatum. Following scopolamine treatment muscarinic receptor density in cerebral cortex, hippocampus and striatum of young rats increased by 34, 57 and 27%, respectively; in brains of aged rats the increase was 41% in cerebral cortex, 43% in hippocampus and nil in striatum. Affinity of muscarinic receptors was not changed by scopolamine treatment. Following chronic ethanol administration there was a 48% increase in cortical muscarinic receptor density in young, but not aged rats. The density of muscarinic receptors in hippocampus and striatum of both young and aged rats was not affected by ethanol treatment. Affinity of receptors in hippocampus of aged, ethanol-treated rats was increased compared to age-matched controls. Adaptative responses of the muscarinic receptor/transducer system to neurotransmitter availability are present in both young and aged rats, both the ethanol-induced response is present only in young animals. This suggests differences in the mechanism of action of ethanol and receptor agonists and antagonists in modulating receptor plasticity.

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.

Previously, it has been suggested that acute ethanol (alcohol) administration can result in concentration-dependent vasoconstriction and decreased cerebral blood flow. Here, we present in vivo results using rapid (240 nm/min) optical backscatter measurements, with an intact cranial preparation in the rat, indicating that acute infusion of ethanol directly into the rat brain rapidly produces dose-dependent vasoconstriction of the cerebral microcirculation associated with a pronounced reduction in tissue blood content, pronounced rises in deoxyhemoglobin, significantly increased levels of reduced cytochrome oxidase and microvascular damage as the dose increases. Furthermore, we present in vivo experiments demonstrating the capability of magnesium ions (Mg(2+)) to attenuate and prevent these deleterious responses. Optical backscatter spectra (500-800 nm) were obtained by directing a single sending and receiving fiber to a portion of the left parietal cranium (in anesthetized rats), shaved to a translucent appearance to facilitate optical penetration. In the absence of added Mg(2+), infusion of a 10% solution of ethanol at 0.34 ml/min ( approximately 26.8 mg/min) produced prompt vasoconstriction as evidenced by a greater than 90% loss of oxyhemoglobin from the field-of-view and increases in levels of reduced cytochrome oxidase to between 50% and >90%. These effects were partially, to nearly completely, attenuated by the addition of MgCl(2) to the infusate containing added ethanol. Of special interest was the observation that attenuation of the vasoconstrictive effect of ethanol by Mg(2+) persisted despite a subsequent ethanol challenge without added Mg(2+). The results obtained demonstrate that, depending on dose, ethanol can produce prompt and severe vasoconstriction of the intact cerebral microcirculation and that infusion of moderate doses of Mg(2+) can largely attenuate and prevent this response. We conclude that appreciable, graded changes in cerebral cytochrome oxidase aa(3), blood volume and the state of hemoglobin occur at minimal tissue levels of ethanol which can be modulated by Mg(2+).

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.

Summary: The potential role of genetic factors in the etiology of posttraumatic and alcohol‐associated seizures was studied in 289 male patients with recurrent seizures and in 174 individuals who had never experienced a seizure. The incidence of seizures in first‐degree relatives of probands was compared with that in relatives of unaffected individuals. Relatives of patients with alcoholassociated seizures had a rate ratio of 2.45 [95% confidence interval (CI) 1.41–4.251, whereas no excess incidence was noted among relatives of posttraumatic epilepsy patients (rate ratio 1.20, 0.64–2.25 CI). Relatives of probands with both antecedents showed an intermediate rate ratio of 1.72 (0.92–3.20 CI). Among probands with alcohol‐associated seizures, the rate ratio of 2.05 for patients with alcohol‐related seizures (i.e., spontaneously occurring seizures in association with chronic alcohol abuse) was slightly higher than that of 1.85 for probands with alcohol withdrawal seizures. Trauma severity had a slight impact on the incidence of affected relatives; patients with severe head injuries had a rate ratio of 0.73 and probands with milder trauma had a rate ratio of 0.99. The results indicate a limited, if any, role of genetic predisposition in development of posttraumatic seizures. Alcoholrelated seizures, however, showed familial aggregation of unprovoked seizures, suggesting an involvement of genetic factors in the origin of such seizures.

Effects of nicotine, administered by continuous infusion via osmotic minipumps, were studied on the operant self-administration of alcohol by rats, using a variable interval (15 s) schedule, and measuring the acquisition, maintenance, extinction and reinstatement of responding for alcohol. Doses of nicotine of 0.25, 1.25 and 7.5 mg/kg/24 h had no significant effects on the maintenance of responding for alcohol, but 5 mg/kg/24 h nicotine resulted in a significant increase in responding on the lever delivering the reward when water was substituted for the alcohol, indicating delayed extinction of responding. During infusion of 2.5 mg/kg/24 h nicotine, responding was significantly greater over the "sucrose-fading" training sessions, during acquisition of responding, when mixtures of alcohol and sucrose were provided as reward. When minipumps infusing 2.5 mg/kg/24 h nicotine were implanted after the alcohol responding had been acquired, the responding for alcohol increase during the first week of nicotine infusion, but corresponding nicotine infusion doses of 0.25, 1.25 and 7.5 had no significant effects. The results indicate that nicotine can increase operant responding for alcohol and this is crucially dependent on the dose of nicotine and the time of testing. The results have implications for the frequently encountered dependence on the combination of alcohol and nicotine.