Advances in alcohol & substance abuse最新文献

It is known that alcohol exposure leads to a decline in brain docosahexaenoate (22:6w3). We hypothesized that alcohol could stimulate the metabolism of this polyunsaturated fatty acid to bioactive products. Several oxidized products of 22:6w3 were indeed observed when rat brain homogenate was incubated with 14C22:6w3 in vitro. A similar group of metabolites was formed in vivo from 14C-22:6w3 injected into the lateral ventricle. These metabolites were characterized by thermospray- and GC/MS as well as by the synthesis of standards using purified enzymes. Platelet lipoxygenase also proved useful in identifying one of the brain metabolites and served as a source of enzyme for preparative studies. Their physiological effects on smooth muscle tone and platelet aggregation will be presented.

Alpha-2-adrenoceptor function has been assessed using the iv clonidine challenge test. During withdrawal clonidine effects on blood pressure, sedation and body temperature were blunted compared with the abstinent state and healthy controls. In contrast the growth hormone response was blunted in both the withdrawing and abstinent alcoholics. These findings suggest that a deficit of alpha-2-inhibitory control is a feature of withdrawal and, in the case of the endocrine response, may persist for some time.

Epidermal growth factor (EGF) is a mitogen which has been shown to stimulate maxillo-facial growth and DNA synthesis. Ethanol has been reported to inhibit cell regeneration in vivo and in vitro and to produce diminished maxillo-facial development in fetal alcohol syndrome. Recent findings from this laboratory have elucidated rapid metabolic changes in the hepatic content of some of the glycolytic intermediates resulting from injection of EGF, ethanol or EGF combined with ethanol in vivo. An immediate effect of EGF in vivo is to increase hepatic tissue content of 3-phosphoglycerate and phosphoenolpyruvate 1.2-1.3 fold when compared to saline treatment. Ethanol however causes a marked fall in the hepatic content of 3-phosphoglycerate and phosphoenolpyruvate 3.2-3.7 fold below saline treated levels. Ethanol in combination with EGF decreases hepatic values for 3-phosphoglycerate and phosphoenolpyruvate 2.0-2.3 fold from saline treated, but elevates the content of phosphoenolpyruvate 1.6 fold over ethanol treatment alone. Such metabolite changes occurring with ethanol treatment have been attributed alternately to redox shifts or to membrane perturbations. We wished to determine whether dimunition of 3-phosphoglycerate and or phosphoenolpyruvate below certain levels perhaps critically necessary for normal mitogenic action of EGF was due in this case to ethanol effects of binding of EGF to the cell membrane.

The chronic effects of fluvoxamine (200 mg per day for 4 weeks) were studied in ten alcoholic organic brain syndrome patients in a double-blind cross-over design. Complete neuropsychological evaluation was performed as well as measurement of neurochemical changes in CSF. Fluvoxamine produced a small but significant improvement in memory performance. An analysis of fluvoxamine minus placebo difference scores showed a significant correlation between memory functioning and CSF 5HIAA levels. Alcohol amnestic syndrome patients who had the highest blood levels of fluvoxamine demonstrated the largest changes in CSF 5HIAA and improvement in memory performance under fluvoxamine. These findings implicate a role of serotonergic mechanisms in alcoholic organic brain syndrome and suggest that with individual titration of the drug dose, fluvoxamine might be a clinically useful agent in the treatment of this syndrome.

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.

Recent studies have demonstrated the presence of immunoreactive oxytocin (OT) and vasopressin (VP), OT and VP receptors and physiological functions for these two hormones in a variety of peripheral tissues, including anterior pituitary gland. The objectives of this study were to determine if (i) OT and VP genes are expressed in rat testis and anterior pituitary gland and (ii) if osmotic stimulation known to modify the regulation of OT and VP genes in hypothalamus, would modify the expression of these genes in rat testis and anterior pituitary gland. Using oligonucleotide probes (courtesy of Drs. M. Brownstein and W. Scott Young, NIMH) corresponding to the VP gene or OT gene and specific fractions of human OT and VP genes (courtesy of Dr. J. Battey, NCI) subcloned in the pGEM-3 riboprobe system, and Northern blot and slot blot techniques, OT and VP mRNAs were found in rat testis and anterior pituitary gland. When adult male rats (SD) were either deprived of drinking water or offered 2% salt solution as a sole source of drinking fluid for 72 hrs, both OT and VP mRNA levels were increased in hypothalamus, anterior pituitary gland and testis. Our data suggest that testis and anterior pituitary gland could also be sites of synthesis of OT and VP and that the same stimulus may regulate these genes in various tissues.