Advances in alcohol & substance abuse最新文献

The first nuclear magnetic resonance spectroscopic study of the canine pancreas is described. Both in-vivo, ex-vivo protocols and nmr observables are discussed. The stability of the ex-vivo preparation based on the nmr observables is established for at least four hours. The spectra obtained from the in-vivo and ex-vivo preparations exhibited similar metabolite ratios, further validating the model. Metabolite levels were unchanged by a 50% increase in perfusion rate. Only trace amounts of phosphocreatine were observed either in the intact gland or in extracts. Acute alcoholic pancreatitis was mimicked by free fatty acid infusion. Injury resulted in hyperamylasemia, edema (weight gain), increased hematocrit and perfusion pressure, and depressed levels of high energy phosphates.

In alcoholism research, two fundamental and closely related questions are: "Why do people drink?" and "Why do some people drink too much?" Humans voluntarily drink alcoholic beverages or self-administer alcohol, more often than not, in a social setting. Environmental factors and how individuals react to them can, therefore, have powerful influences on drinking behavior. On the other hand, the neuropsychopharmacological actions of ethanol and how different individuals react to them can be important biological determinants. Ethanol's action is biphasic, i.e., it can be reinforcing (rewarding) in the low concentration range, but aversive at high concentrations. Perception by the individual of the reinforcing actions of ethanol might be expected to maintain alcohol-seeking behavior, whereas aversive effects would be expected to extinguish this behavior. Identification of the environmental and biological variables that promote and maintain alcohol-seeking or alcohol self-administration behavior is key to our understanding of the disorder alcoholism itself.

Ethanol exposure leads to a loss in membrane polyunsaturated fatty acids (PUFA). It is proposed that polyunsaturated species of phospholipids are not randomly distributed, but are concentrated in the cytosolic leaflets of the plasma membrane and are preferentially associated with membrane proteins. These lipids affect the physical state of environments surrounding membrane proteins and thereby serve to regulate many cellular functions. Disruption of these environments may occur even when a small percentage of total polyunsaturates is lost due to ethanol exposure. One possible mechanism of ethanol-induced polyunsaturate loss may be activation of a phospholipase A2 enzyme which is selective for these species of phospholipids. Fatty acids released would stimulate the production of prostaglandins and/or leukotrienes. Similarly, the released docosahexaenoate can be metabolized by rat brain to leukotriene-like compounds which are biologically active in smooth muscle systems. This metabolism is stimulated by ethanol in human platelets, in vitro.

Recent progress toward a systematic pathophysiological model of alcoholism has led to identification of two distinct subtypes of alcoholism. These subtypes may be distinguished in terms of distinct alcohol-related symptoms, personality traits, ages of onset, and patterns of inheritance. Type 1 alcoholism is characterized by anxious (passive-dependent) personality traits and rapid development of tolerance and dependence on the anti-anxiety effects of alcohol. This leads to loss of control, difficulty terminating binges once they start, guilt feelings, and liver complications following socially encouraged exposure to alcohol intake. In contrast, type 2 alcoholism is characterized by antisocial personality traits and persistent seeking of alcohol for its euphoriant effects. This leads to early onset of inability to abstain entirely, as well as fighting and arrests when drinking. Empirical findings about sex differences, ages of onset, associated personality traits, and longitudinal course are described in a series of adoption and family studies in Sweden and the United States. Implications for future research and clinical practice are discussed.

It has been previously reported that ethanol alters the level of polyunsaturated fatty acids, and this may be related to alteration of membrane physical properties. Therefore, developing a technique to efficiently analyze lipid molecular species is of value for alcohol research. A new technique which can provide detailed structural information for most major lipid classes has been developed in our laboratory using thermospray liquid chromatography/mass spectrometry (LC/MS). In this technique, on-line LC separation is achieved with a conventional flow rate and the LC effluent is carried into the mass spectrometer via a heated capillary where it is vaporized and ionized. The results thus obtained for the major lipid classes including fast separation methods and quantitative aspects will be presented.

The acute in vitro effects of ethanol on cerebral cortical adenylate cyclase activity and beta-adrenergic receptor characteristics suggested a site of action of ethanol at Gs, the stimulatory guanine nucleotide binding protein. After chronic ethanol ingestion, the beta-adrenergic receptor appeared to be uncoupled (i.e., the form of the receptor with high affinity for agonist was undetectable), and stimulation of adenylate cyclase activity by isoproterenol or guanine nucleotides was reduced, suggesting an alteration in the properties of Gs. To further characterize this change, cholera and pertussis toxin-mediated 32P-ADP-ribosylation of mouse cortical membranes was assessed in mice that had chronically ingested ethanol in a liquid diet. 32P-labeled proteins were separated by SDS-PAGE and quantitated by autoradiography. There was a selective 30-50% decrease in cholera toxin-induced labeling of 46 kDa protein band in membranes of ethanol-fed mice, with no apparent change in pertussis toxin-induced labeling. The 46 kDa protein has a molecular weight similar to that of the alpha subunit of Gs, suggesting a reduced amount of this protein or a change in its characteristics as a substrate for cholera toxin-induced ADP-ribosylation in cortical membranes of ethanol-fed mice.

Treatment with 5HT reuptake inhibitors has been shown to attenuate ethanol consumption in both animals and humans. These experiments investigate in mice the interactions of the 5HT reuptake inhibitors fluoxetine, citalopram and fluvoxamine and the NA uptake inhibitor desipramine with ethanol in the holeboard test and the elevated plusmaze test of anxiety. Ethanol (2.4 g/kg) increased activity both in the holeboard and on the plusmaze, decreased both the number and duration of head-dips in the holeboard, and increased both the percentage time and percentage entries on to the open-arm of the plusmaze (reflecting its anxiolytic properties). On their own, the selective 5HT uptake inhibitors fluoxetine, fluvoxamine, and citalopram and the NA uptake inhibitor desipramine (10-20 mg/kg) did not significantly alter any of the behavioral measures. The only consistent interaction was seen with fluoxetine which reduced ethanol's anxiolytic effects at the 20 mg/kg dose without altering ethanol's effects on exploration or locomotion. The results suggest that the attenuation of ethanol's anxiolytic properties by fluoxetine may not be serotonin related since other 5HT reuptake inhibitors did not show this effect at the doses used.

Hormonal release from neurosecretory cells appears to be regulated in part by ionic currents. Because ethanol was shown to alter the release of melatonin from the cultured pineal gland, the ionic currents present in pineal cells were characterized using the whole-cell patch clamp technique. The macroscopic ionic current observed in standard solutions was dominated by an outward current component. Study of this outward component in a solution without added external Ca2+ revealed the existence of two distinct outward currents. Depolarizing command voltages from a holding potential of -100 mV activated a fast outward current which reached a peak within 20 ms and completely decayed in about 150 ms. The second outward current isolated from a holding potential of -50 mV activated at potentials positive to -20 mV. In the presence of 2 mM external Ca2+ the I-V relationship did not display a region of negative slope conductance suggesting that Ca2+-activated K+ current did not contribute significantly to the outward current. A small Ca2+ inward current was observed when these two outward components were eliminated. These results indicate that acutely dissociated pineal cells display two distinct K+ outward currents: (i) a transient current similar to the A current (IA); and (ii) a slowly activating, sustained current similar to the delayed rectifier (IK). Thus, the characterization of ionic currents in the pineal cell is of importance because they may be a target for acute and chronic ethanol actions.

Previous work showed that chronic ethanol ingestion by C57BL mice resulted in reduced stimulation of cerebral cortical adenylate cyclase (AC) activity by isoproterenol (ISO) and guanine nucleotides (GN). To investigate the mechanism of this change we have assessed the effect of chronic ethanol ingestion on agonist and antagonist binding to BAR in cerebral cortex (mainly beta 1-AR) and cerebellum (mainly beta 2-AR). C57BL mice were fed ethanol in a liquid diet for seven days and were withdrawn for various intervals. Agonist (ISO) binding data were best fit by a two-site model (high and low affinity states) in cortical membranes of control mice. GN induced conversion to a one site model (low affinity state). At the time of withdrawal, ISO binding data in cortical membranes were best fit by a one-site model even in the absence of GN. Antagonist binding was not affected. These results resemble those seen after heterologous desensitization, indicating "uncoupling" of receptor and AC. Control cerebellar ISO binding data were similar to cortical data. Chronic ethanol ingestion, however, did not produce data fit by a one site model in cerebellum. The affinity for ISO of the high affinity state of the BAR was significantly decreased at the time of withdrawal. ISO-stimulated AC-activity in cerebellar membranes was not affected by chronic ethanol ingestion, indicating that, in contrast to cerebral cortex, the cerebellar BAR was not uncoupled from AC.

This short review examines recent findings on neurochemical differences between alcoholics and various control populations. Particular emphasis is given to clinical variables which affect concentrations of neurotransmitter metabolites in the cerebrospinal fluid, and which have to be controlled in order to make meaningful comparisons between various diagnostic groups. The review focuses on two of the major monoamine transmitters, serotonin and norepinephrine, and excludes neurotransmitters and modulators such as dopamine, acetylcholine, peptides, prostaglandins, amino acids and purines, since their significance to alcoholism is currently less well understood.