Advances in alcohol & substance abuse最新文献

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.

Plasma D,L-2,3-butanediol was measured in 53 controls and 50 patients with alcoholic cirrhosis, none of whom had measurable amounts of blood ethanol. Thirteen of 50 samples from patients with alcoholic cirrhosis had measurable D,L-2,3-butanediol. (range less than 5-154 microM). In one patient with alcoholic cirrhosis who had been abstinent from ethanol for over 5 years plasma levels of D,L-2,3-butanediol ranged between 154 and 211 microM over a one-year period. Only one of the 53 control subjects had detectable levels of D,L-2,3-butanediol. Although it has previously been reported that 2,3-butanediol is present in alcoholics consuming distilled spirits (Rutstein et al. (1983) Lancet ii, 534), this is the first report of the persistent presence of these compounds in alcoholics in the absence of ethanol. Clearly in abstinent alcoholics the presence of 2,3-butanediol is not due to the ingestion of undistilled spirits nor is it likely to arise directly from the metabolic products of ethanol. The presence of D,L-2,3-butanediol in patients with alcoholic cirrhosis and its absence in control subjects suggests that this compound may be a marker of some forms for alcoholism.

Specific polyclonal antisera against microsomal ethanol-inducible cytochrome P450 (P450j, P450IIE) were prepared and utilized to isolate cDNA for P450j from lambda gt11 cDNA libraries. The longest cDNAs encoding P450j of rat and human were completely sequenced. The rat P450j sequence was compared to those of other P450s (P450II gene family members) to determine the structural similarity. Southern-blot analysis of rat and human genomic DNAs verified that only a single gene shared extensive homology with P450j. Cloned P450j cDNA and antibodies were used to study the expression of P450j gene during development and by various inducers as well as in pathological conditions. By combination of cDNA hybridization and immunoblot analyses, three types of P450j gene expression were observed: transcriptional activation during development; post-transcriptional activation (probably via protein stabilization) by various inducers such as pyrazole, 4-methylpyrazole, acetone, and ethanol; and mRNA stabilization in diabetic and starved animals. These three different types of P450j induction appeared to be present not only in liver but also in lung and kidney tissues.

We have previously demonstrated that single-dose ethanol administration enhanced plasma levels of ACTH, beta-endorphin, corticosterone (CS) and catecholamines. Since the secretion of proopiomelanocortin-derived peptides (e.g., ACTH, beta-endorphin) can be influenced by catecholamines and vasopressin in addition to the primary physiological regulator, corticotrophin-releasing hormone, we have attempted to determine whether or not the ethanol-induced activation of the hypothalamic-pituitary-adrenal axis (HPAA) could in part be mediated via either epinephrine or vasopressin (AVP) secretion. The selective neutralization of AVP through the administration of AVP antiserum failed to block the ethanol-induced secretion of either ACTH or CS. In addition, adrenal demedullation did not significantly attenuate the ethanol-induced increase of ACTH and CS. It would appear that neither adrenal medulla-derived epinephrine nor median eminence-derived AVP mediates ethanol's activation of the HPAA.

The role of gender as a variable that might affect the metabolism of ethanol and thus the consequences of ethanol metabolism is reviewed. First, the pharmacodynamics of ethanol are reviewed. Specific differences between males and females relative to ethanol pharmacokinetic parameters are discussed including gender differences in the volume of distribution and putative hormonal effects on achieved blood alcohol levels. In addition, attention is directed toward the metabolic capacity of alcohol dehydrogenase and the microsomal ethanol oxidizing system with respect to effects of both sex differences and hormonal manipulations on the activities of these ethanol metabolizing enzymes. Finally, the data upon which the concept of sex-related differences in susceptibility to alcohol induced end organ failure are presented.

The objective of this project has been to develop a sensitive and specific assay for prostaglandins in human cerebrospinal fluid (CSF) from patients with alcoholism and appropriate controls using gas chromatography/mass spectrometry. This study was initiated because numerous literature reports strongly suggest that a relationship exists between ethanol's central nervous system effects and the central production of prostaglandins. In both human and animal studies, administration of prostaglandin synthesis inhibitors prior to administration of ethanol attenuated central nervous system effects of ethanol. Samples from alcoholics after a three week period of abstinence and normals contained none of the measured prostaglandins (PGE2, PGE1, PGF1a, PGF2a, 6-keto-PGF1a) at a concentration more than twice the limit of quantification (3 pg/mL CSF). Comparison of GC/MS and radioimmunoassay methods provided further validation for these results. Literature reports of much higher levels of prostaglandins in normal controls, i.e., tens to hundreds of pg/mL CSF, appear to be incorrect. Examination of monkey CSF provided a positive control, since several of the prostaglandins were easily quantifiable in these samples.

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 acute effects of ethanol on skilled motor functions were examined in male social drinkers, under four doses ranging from 0 (placebo) to 1.05 g/kg lean body weight. The movement entailed a forewarned choice transitive motion of the arm and hand, aimed at a flanking target. Performance measures disclosed only small effects of ethanol on speed and accuracy of movement. The simultaneously-recorded movement-related brain potentials disclosed decreased involvement of frontal and posterior brain areas, suggesting that ethanol disrupted the planning and regulation of movement despite the overall preservation of reaction speed.

Serotonin is an important neurotransmitter that may be involved in ethanol preference and dependence. It is possible to label the serotonin uptake site in brain using the tricyclic antidepressant imipramine, but this also binds to other sites. We have used the new high-affinity uptake blocker paroxetine to define binding to this site and report it to have advantages over imipramine as a ligand.

Rats were exposed to alcohol vapors by an inhalation technique and blood pressure and its reactivity and platelet aggregation were measured. Acute exposure to alcohol levels which produced moderate blood alcohol concentration (BAC) was associated with increased vascular production of prostacyclin (PGI2) and plasma catecholamines, whereas platelet production of thromboxane (TXA2) decreased. Blood pressure is elevated in these animals, however, the platelet aggregating and pressor effects of noradrenaline (NE) were decreased. Chronic exposure to high BAC is associated with a dramatic reduction in vascular and platelet prostaglandin (PG) production and a marked increase in plasma catecholamine levels. Platelet aggregation decreased in these animals, however, the pressor effect of TXA2 and NE was significantly increased. The fatty acid precursors to PG were reduced by 50% in the lipid extracts of these preparations. These findings suggest that alterations in fatty acid metabolism may lead to a functional deficiency in PG production from dependent rats. Qualitative differences may exist between acute and chronic exposure with respect to the cardiovascular state. Locally produced PG and circulating catecholamines may mediate alcohol-induced alterations in vascular smooth muscle tone and platelet aggregation.