Frequency selective effects of alcohol on auditory detection and frequency discrimination thresholds.
(25/1532)
In the first of two experiments, the effects of ethyl alcohol on monaural and binaural thresholds for pure tones were measured for a range of frequencies. The results showed a frequency-specific effect in which low frequencies were more severely affected than higher ones. Also, monaural thresholds tended to be more affected by alcohol than binaural ones. The second experiment extended this exploration by measuring frequency discrimination at several different frequencies. In this case, we also obtained a frequency-dependent effect: the increase in discrimination thresholds above 1000 Hz was three times greater than that for lower frequencies. The data suggest that the choice of stimuli may influence the ability to detect changes in auditory performance after alcohol and may account in part for the differences among earlier studies. The results are consistent with the hypothesis that alcohol is acting centrally, at the level of mechanisms involved in the temporal and binaural summation of auditory signals, rather than influencing peripheral structures. (+info)
Psychopathology in alcohol withdrawal: relationship to alpha2-adrenoceptor function.
(26/1532)
The possible relationship between postsynaptic alpha2-adrenoceptor function, as assessed by growth hormone (GH) response to clonidine (CLON; 1.5 or 2.0 microg/kg i.v.), and psychopathology was investigated in 30 patients with alcohol-dependence in the early withdrawal period. Excluding patients with high baseline GH, 23 of the 26 patients had blunted GH responses to CLON and 57% moderate or severe depression at day 1 after the end of alcohol intake. After 1 week, the GH responses to CLON remained blunted in 20 of 21 retested patients, whereas the depression and anxiety remitted in all but two patients. The results do not support any relationship between postsynaptic alpha2-adrenoceptor function and symptoms of psychopathology in alcohol withdrawal. (+info)
A pilot study of a new chicken model of alcohol-induced cardiomyopathy.
(27/1532)
BACKGROUND: Excessive alcohol consumption is recognized as a common cause of left ventricular (LV) dysfunction. It is currently thought that 36% of all cases of dilated cardiomyopathy are due to excessive alcohol intake. Suitable animal models are needed to study the pathogenic mechanisms of ethanol-induced LV dysfunction. We have therefore created a new model of ethanol-induced LV dysfunction in the chicken. METHODS: For 12 weeks, adult chickens were given, twice a day, by gavage, 73% of their total calculated daily water intake containing a 20% ethanol concentration. Twenty percent ethanol also was placed in the water and provided ad libitum. Control chickens received the same volume of water by gavage twice a day without ethanol. Water without ethanol was given ad libitum to control birds. RESULTS: Our study shows that after a relatively short duration of ethanol ingestion, chickens developed LV dilatation and LV dysfunction. The serum concentrations of ethanol attained in this new model were similar to those reported in humans. Furthermore, unlike other currently available animal models of ethanol-induced cardiac disease, this model demonstrates myocyte hypertrophy, interstitial fibrosis, and myocytolysis, similar to observations in human ethanol-induced cardiac dysfunction. CONCLUSIONS: We conclude that this new avian model should provide a useful tool for investigating the mechanism(s) and pathophysiology of ethanol-induced dilated cardiomyopathy and heart failure. (+info)
Adaptive responses of gamma-aminobutyric acid neurons in the ventral tegmental area to chronic ethanol.
(28/1532)
We have recently identified a homogeneous population of gamma-aminobutyric acid (GABA)-containing neurons in the ventral tegmental area (VTA), an area implicated in the reinforcing properties of alcohol. We evaluated the effects of local and systemic ethanol on VTA GABA neuron spontaneous activity in ethanol naive and chronically treated freely behaving rats and in anesthetized rats. In freely behaving animals, acute i.p. administration of 0.2 to 2.0 g/kg ethanol reduced the firing rate of VTA GABA neurons. Chronic administration of 2.0 g/kg i.p. ethanol enhanced baseline activity of VTA GABA neurons and induced tolerance to ethanol inhibition of their firing rate. In a separate group of freely behaving animals, tolerance to 0.4 to 2.0 g/kg i.p. ethanol-induced inhibition of VTA GABA neuron firing rate was observed following 2 weeks of chronic exposure to ethanol vapors producing intermittent blood alcohol levels of 158 mg/100 ml. In acute studies in halothane-anesthetized animals, ethanol applied locally into the VTA decreased the spontaneous firing rate of VTA GABA neurons, whereas systemic ethanol produced an early inhibition followed by a late excitation at 30 to 60 min after the ethanol injection, suggesting that ethanol modulation of an extrinsic input may excite VTA GABA neurons. Tolerance to local ethanol inhibition of VTA GABA neuron firing rate was produced by 2 weeks of chronic exposure to intermittent ethanol vapors. These results demonstrate the marked sensitivity of these neurons to ethanol and suggest that chronic ethanol administration produces selective adaptive circuit responses within the VTA or in extrategmental structures that regulate VTA GABA neuron activity. (+info)
Interactive role for neurosteroids in ethanol enhancement of gamma-aminobutyric acid-gated currents from dissociated substantia nigra reticulata neurons.
(29/1532)
Although previous in vivo electrophysiological studies demonstrated a consistent ethanol enhancement of gamma-aminobutyric acid (GABA) responsiveness from substantia nigra reticulata (SNR) neurons, ethanol applied in vitro to dissociated neurons from the SNR had an inconsistent effect on GABA function. One source for the disparity between these contrasting in vivo and in vitro results could be an endogenous factor (acting on an auxiliary site on GABA(A) receptors) that was not available to the isolated SNR neurons. Because neurosteroids are present in vivo and act on an auxiliary site, it was hypothesized that the presence of a neurosteroid was important for a consistent effect of ethanol on GABA responsiveness from neurons studied in vitro. Alone, the neurosteroid analog alphaxalone produced a significant, concentration-related enhancement of GABA responsiveness from isolated SNR neurons. In contrast to an inconsistent action of 100 mM ethanol on GABA responsiveness in the absence of alphaxalone, the presence of 30 and 100 nM alphaxalone resulted in the majority of isolated neurons responding to this ethanol level. At a concentration of alphaxalone as low as 30 nM, ethanol produced a robust concentration-related increase in GABA-gated currents from this cell type. The neurosteroid 3alpha, 5alpha-tetrahydrodeoxycorticosterone (100 nM) also permitted a reliable concentration-dependent ethanol enhancement of responses to GABA from SNR cells, indicative that the effects of alphaxalone were not unique. This consistent neurosteroid-induced ethanol enhancement of GABA responsiveness from dissociated SNR neurons supports the view that neurosteroids may play a key role in the action of ethanol on postsynaptic GABA(A) receptor function. (+info)
Ethanol-induced barrier dysfunction and its prevention by growth factors in human intestinal monolayers: evidence for oxidative and cytoskeletal mechanisms.
(30/1532)
Exposure of intestinal mucosa to ethanol (EtOH) disrupts barrier function and growth factors [epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha)] are protective, but the mechanisms remain obscure. Accordingly, we sought to determine whether the molecular mechanism of EtOH-induced intestinal barrier dysfunction involves oxidative stress and disassembly of microtubules and whether the mechanism of protection by EGF or TGF-alpha involves prevention of these alterations. To this end, human colonic (Caco-2) monolayers were exposed to 0 to 15% EtOH with or without pretreatment with EGF or TGF-alpha (10 ng/ml) or with oxidative or cytoskeletal modulators. Effects on cell viability, barrier function, tubulin (microtubules), and oxidative stress were then determined. Cells were also processed for immunoblots of polymerized tubulin (S2; index of stability) and the monomeric tubulin (S1; index of disruption). EtOH dose-dependently decreased the stable S2 polymerized tubulin and concomitantly increased measures of oxidative stress, including oxidation and nitration of tubulin, fluorescence of dichlorofluorescein, and inducible nitric oxide synthase activity. EtOH also dose-dependently disrupted barrier function and extensively damaged microtubules, and these effects were prevented by pretreatment with antioxidant scavengers: L-cysteine, superoxide dismutase, and L-N(6)-1-iminoethyl-lysine (an inducible nitric oxide synthase inhibitor). In monolayers exposed to EtOH, pretreatment with EGF or TGF-alpha prevented the oxidation and nitration of tubulin, increases in the levels of the unstable S1 tubulin, disruption of microtubules, and barrier dysfunction. A microtubule stabilizer (paclitaxel,Taxol) mimicked, in part, the effects of EGF and TGF-alpha, whereas a microtubule disruptive drug (colchicine) prevented the protective effects of these growth factors. We concluded that mucosal barrier dysfunction induced by EtOH involves oxidative stress, which causes the disassembly of the microtubule cytoskeleton. Protection by EGF and TGF-alpha involves the prevention of these EtOH-induced alterations in microtubules. (+info)
Chronic alcohol feeding impairs hepatic translation initiation by modulating eIF2 and eIF4E.
(31/1532)
The present study examined potential cellular mechanisms responsible for the inhibition of protein synthesis in liver after chronic alcohol consumption. Rats were maintained on an alcohol-containing diet for 14 wk; control animals were fed isocalorically. Hepatic ATP content was not different in alcohol-fed and control animals. No alcohol-induced reduction in total hepatic RNA content (an estimate of ribosomal RNA) was detected, suggesting that alcohol decreased translational efficiency. Alcohol feeding increased the proportion of 40S and 60S ribosomal subunits in the nonpolysome-associated fraction by 30%. To identify mechanisms responsible for the impairment in initiation, several eukaryotic initiation factors (eIF) were analyzed. Alcohol feeding decreased hepatic eIF2B activity by 36%. This reduction was associated with a 20% decrease in eIF2Bepsilon content and a 90% increase in eIF2alpha phosphorylation. Alcohol also dramatically influenced the distribution of eIF4E. Compared with pair-fed control values, alcohol feeding increased the amount of eIF4E present in the inactive 4E-binding protein 1 (4E-BP1). eIF4E complex by 80% and decreased binding of eIF4G to eIF4E by 70%. However, the phosphorylation status of 4E-BP1 and eIF4E was not altered by alcohol. Although the plasma concentrations of threonine, proline, and citrulline were mildly decreased, the circulating amount of total amino acids was not altered by alcohol feeding. In summary, these data suggest that chronic alcohol consumption impairs translation initiation in liver by altering eIF2B activity as well as eIF4F function via changes in eIF4E availability. (+info)
Combined effects of diethylpropion and alcohol on locomotor activity of mice: participation of the dopaminergic and opioid systems.
(32/1532)
The widespread consumption of anorectics and combined anorectic + alcohol misuse are problems in Brazil. In order to better understand the interactive effects of ethanol (EtOH) and diethylpropion (DEP) we examined the locomotion-activating effects of these drugs given alone or in combination in mice. We also determined whether this response was affected by dopamine (DA) or opioid receptor antagonists. A total of 160 male Swiss mice weighing approximately 30 g were divided into groups of 8 animals per group. The animals were treated daily for 7 consecutive days with combined EtOH + DEP (1.2 g/kg and 5.0 mg/kg, ip), EtOH (1.2 g/kg, ip), DEP (5.0 mg/kg, ip) or the control solution coadministered with the DA antagonist haloperidol (HAL, 0.075 mg/kg, ip), the opioid antagonist naloxone (NAL, 1.0 mg/kg, ip), or vehicle. On days 1, 7 and 10 after the injections, mice were assessed in activity cages at different times (15, 30, 45 and 60 min) for 5 min. The acute combination of EtOH plus DEP induced a significantly higher increase in locomotor activity (day 1: 369.5 +/- 34.41) when compared to either drug alone (day 1: EtOH = 232.5 +/- 23.79 and DEP = 276.0 +/- 12.85) and to control solution (day 1: 153.12 +/- 7.64). However, the repeated administration of EtOH (day 7: 314.63 +/- 26.79 and day 10: 257.62 +/- 29.91) or DEP (day 7: 309.5 +/- 31.65 and day 10: 321.12 +/- 39. 24) alone or in combination (day 7: 459.75 +/- 41.28 and day 10: 427. 87 +/- 33.0) failed to induce a progressive increase in the locomotor response. These data demonstrate greater locomotion-activating effects of the EtOH + DEP combination, probably involving DA and/or opioid receptor stimulation, since the daily pretreatment with HAL (day 1: EtOH + DEP = 395.62 +/- 11.92 and EtOH + DEP + HAL = 371.5 +/- 6.76; day 7: EtOH + DEP = 502.5 +/- 42.27 and EtOH + DEP + HAL = 281.12 +/- 16.08; day 10: EtOH + DEP = 445.75 +/- 16.64 and EtOH + DEP + HAL = 376.75 +/- 16.4) and NAL (day 1: EtOH + DEP = 553.62 +/- 38.15 and EtOH + DEP + NAL = 445.12 +/- 55.67; day 7: EtOH + DEP = 617.5 +/- 38.89 and EtOH + DEP + NAL = 418.25 +/- 61.18; day 10: EtOH + DEP = 541.37 +/- 32.86 and EtOH + DEP + NAL = 427.12 +/- 51.6) reduced the locomotor response induced by combined administration of EtOH + DEP. These findings also suggest that a major determinant of combined anorectic-alcohol misuse may be the increased stimulating effects produced by the combination. (+info)