• Energy Research

This is a preliminary study to explore the theory that there may be abnormalities of the benzodiazepine receptor, or a possible endogenous inverse agonist ligand in alcohol withdrawal. The benzodiazepine antagonist flumazenil was administered to 8 alcoholics in early withdrawal in a double blind placebo controlled design. Self ratings of mood and physical symptoms, and observer ratings of withdrawal symptoms revealed differences in the effects of flumazenil and placebo. Flumazenil had an immediate slight anxiogenic action which was short-lived. It then appeared to ameliorate withdrawal symptoms, quite markedly in 2 patients.

It has recently been claimed that RO 15-4513 selectively opposes some of the behavioral actions of ethanol. Our studies on the intrinsic effects of this compound have shown it to be proconvulsant and to reduce exploratory behavior in mice. In these respects RO 15-4513 resembles a benzodiazepine receptor partial inverse agonist. Such intrinsic actions may well explain its alcohol-antagonizing properties, and argue against its potential in humans. In addition to partially reversing the effects of ethanol, RO 15-4513 also partially reverses the behavioral effect of a barbiturate and completely reverses the effects of a benzodiazepine.

Preclinical evidence suggests the α5 subtype of the GABA-benzodiazepine receptor is involved in some of the actions of alcohol and in memory. The positron emission tomography (PET) tracer, [11C]Ro15 4513 shows relative selectivity in labelling the α5 subtype over the other GABA-benzodiazepine receptor subtypes in limbic regions of the brain. We used this tracer to investigate the distribution of α5 subtype availability in human alcohol dependence and its relationship to clinical variables. Abstinent (>6 weeks) alcohol-dependent men and healthy male controls underwent an [11C]Ro15 4513 PET scan. We report [11C]Ro15 4513 brain uptake for 8 alcohol-dependent men and 11 healthy controls. We found a significant reduction in [11C]Ro15 4513 binding in the nucleus accumbens, parahippocampal gyri, right hippocampus and amygdala in the alcohol-dependent compared with the healthy control group. Levels of [11C]Ro15 4513 binding in both hippocampi were significantly and positively associated with performance on a delayed verbal memory task in the alcohol-dependent but not the control group. We speculate that the reduced limbic [11C]Ro15 4513 binding seen here results from the effects of alcohol, though we cannot currently distinguish whether they are compensatory in nature or evidence of brain toxicity.

The interaction of a highly potent and selective alpha-2 adrenoceptor antagonist, atipamezole with ethanol was investigated in tests assessing a number of ethanol's behavioral effects. Atipamezole antagonized ethanol's effects on directed exploration in a holeboard test, reduced observer-rated intoxication and also reduced the duration of loss of righting reflex caused by ethanol. Similar effects were produced by another alpha-2 adrenoceptor antagonist idazoxan. The magnitude of the effects was comparable to that produced in the same animal models by the imidazodiazepine Ro 15-4513, which antagonizes ethanol by an action at central benzodiazepine receptors. Whereas Ro 15-4513 possesses marked behavioral effects on its own, atipamezole is comparatively inactive in all paradigms so far tested. The data suggest that alpha-2 adrenoceptors can play an important role in modulating the intoxicating effects of ethanol.

The authors have investigated the function of the hypothalamic-pituitary-adrenocortical (HPA) axis during and after withdrawal from alcohol. 24 hour rhythms of cortisol were abnormal in that elevated levels were seen throughout the day in patients with moderate to severe, but not mild, withdrawal. This abnormality of circadian secretion of cortisol, which is similar to that seen in Cushing's syndrome and post-operative trauma, returned to normal after a period of one week of abstinence on their in-patient ward. Such excessive secretion of cortisol may explain some of the complications of chronic alcoholism.

The ability of various benzodiazepine receptor ligands to antagonize the anticonvulsant action of ethanol was investigated using intravenous infusion of the GABA antagonist bicuculline. The partial inverse agonists FG 7142, RO 15-4513 and RO 15-3505 produced dose-related reductions in seizure threshold. These compounds also partially reversed the anticonvulsant action of ethanol. However, the magnitude of the effects in each case was only equivalent to the reduction in seizure threshold caused by each compound when administered alone. This is the proconvulsant effect of each compound merely subtracted from the anticonvulsant effect of ethanol. ZK 93426, a benzodiazepine receptor antagonist which alone failed to alter seizure threshold, did not affect the anticonvulsant action of ethanol. Both RO 15-4513 and RO 15-3505 also lowered the seizure threshold of barbiturate-treated mice, again in a subtractive fashion. The ability of RO 15-4513 and other inverse agonists to antagonize the anticonvulsant effect of ethanol appears to result from their intrinsic proconvulsant properties.

The calcium antagonists nimodipine and dantrolene were compared with diazepam in an animal model of tolerance and physical dependence upon ethanol. Nimodipine and dantrolene were both effective in suppressing withdrawal tremors but diazepam was clearly superior to both agents. These results suggest that the ethanol withdrawal syndrome is only partially mediated by increased calcium flux.

The purpose of this chapter is to bring together some of the recent research that has significantly increased our knowledge of the mechanisms underlying the actions of alcohol in the body, including absorption and metabolism. One particular field of growth is that of the actions of alcohol in the brain. In the past few years there have been a number of important advances in our understanding of the mechanisms by which alcohol produces sedation, intoxication and pleasure as well as those processes which contribute to its addictive properties. Progress has also been made in unravelling the mechanisms of tolerance and physical withdrawal and these studies have also thrown light on the basis of the neurotoxic effects of alcohol. Similarly in the periphery new ideas about the toxic tissue damaging properties of alcohol have been developed.