Relationship between central serotonergic neurotransmission and reduction in alcohol intake by citalopram.

The relationship between the effect of citalopram on alcohol intake and central serotonergic neurotransmission, as assessed by prolactin (PRL) response to fenfluramine, was investigated in 17 male heavy drinkers. A positive correlation was obtained, suggesting that the status of central serotonergic neurotransmission in individuals is associated with the treatment response to citalopram. When the group of subjects were divided into those with high and low PRL response (above and below median, respectively) to fenfluramine, those with high PRL response had a significant reduction in alcohol intake during citalopram treatment, whereas those with low PRL response had no such effect. Thus, in subjects with evidence of unimpaired or only slightly impaired central serotonergic neurotransmission (high PRL response) citalopram may have beneficial effect on alcohol consumption, whereas in those with more evidently impaired serotonergic neurotransmission (low PRL response) citalopram treatment may have no effect on or may even increase the alcohol consumption.     

Prolactin response to d-fenfluramine in combat-related post-traumatic stress disorder

Central serotonergic function can be investigated by measuring the prolactin response to the serotonin releasing/uptake agent, d-fenfluramine. This study investigated the effect of diagnosis, depressive symptoms and history of alcohol or tobacco abuse or dependence on the d-fenfluramine test in combat-related post-traumatic stress disorder (PTSD). Male, non-hospitalized combat-exposed veterans diagnosed with PTSD (DSM-III-R) and a similarly aged combat-exposed control group were assessed for both PTSD and depressive symptoms and prolactin responses to a 30-mg d-fenfluramine challenge test. Ninety-five subjects were studied; 23 were controls, 46 subjects met the criteria for current PTSD and 26 for past PTSD. There were no significant differences between the three groups for baseline prolactin, peak prolactin, and time to reach peak, delta prolactin or area under the curve of the prolactin vs. time curve. Depressive symptoms and history of alcohol or tobacco abuse or dependence did not have a confounding effect on the prolactin responses to d-fenfluramine. This study suggests that a blunted prolactin response to d-fenfluramine may be a consequence of combat exposure rather than PTSD. To confirm this, further studies involving both healthy and combat-exposed control groups in addition to subjects with PTSD of similar ages are required.     

Is long-term heavy alcohol consumption toxic for brain serotonergic neurons? Relationship between years of excessive alcohol consumption and serotonergic neurotransmission.

The relationship between years of excessive alcohol consumption and central serotonergic neurotransmission, as assessed by the prolactin (PRL) response to D-fenfluramine, was investigated in 22 male alcohol-dependent subjects. A negative correlation was obtained, that is, the longer duration of excessive alcohol consumption the lower PRL response to D-fenfluramine. It is therefore suggested that long duration of excessive alcohol consumption in alcohol-dependent subjects causes a reduction in central serotonergic neurotransmission, possibly by a toxic effect of alcohol on serotonin neurons. The relationship between depressive and anxiety symptoms during on-going drinking and the PRL response to D-fenfluramine was also investigated. No such correlations were obtained, suggesting that reduction in central serotonergic neurotransmission does not pre-dispose to the development of depressive and anxiety symptoms, at least in relation to on-going drinking in alcohol-dependent subjects.     

Alcohol self-administration by female macaque monkeys: a model for study of alcohol dependence, hyperprolactinemia and amenorrhea

Chronic alcohol dependence produces persistent amenorrhea in alcoholic women and female Macaque monkeys but the mechanism is unknown. In one amenorrheic alcohol-dependent monkey, prolactin levels increased from 16.5 to 63 ng/ml during chronic, high-dose alcohol self-administration (3.4 g/kg/day) and immunocytochemical examination of the anterior pituitary showed apparent hyperplasia of the lactotrophs. These data suggested that hyperprolactinemia might contribute to alcohol-induced amenorrhea. Four amenorrheic cycles (85-194 days) from two other alcoholic female monkeys that self-administered an average of 2.97 to 4.4 g/kg/day of alcohol were also studied. Each monkey became amenorrheic during the first menstrual cycle that alcohol was available. One monkey developed galactorrhea during a 97-day amenorrheic cycle when alcohol self-administration averaged 3.35 g/kg/day. Although prolactin levels were intermittently elevated above 20 ng/ml, average levels during these amenorrheic cycles (14.7 +/- 1.8 to 19.6 +/- 1.5 ng/ml) did not differ significantly from prolactin levels during normal ovulatory menstrual cycles when no alcohol was available (19.7 +/- 0.36 ng/ml). There was a negative correlation between daily alcohol dose and prolactin levels (p less than .01). High-dose alcohol self-administration was often associated with low normal prolactin levels, but a relative fall in alcohol dose was usually associated with elevated prolactin levels. These data suggest that both alcohol intoxication and relative alcohol withdrawal may alter basal prolactin levels. LH levels were significantly lower during amenorrheic cycles (16.9 +/- 1.2 to 24 +/- 1.4 ng/ml) than during nonalcohol control cycles (28 +/- 1.2 to 30 +/- 2.2 ng/ml) (p less than .001). These data are consistent with clinical data that suggest that hypothalamic amenorrhea is associated with suppression of gonadotropin secretory activity.     

Alcohol dehydrogenase: an autoantibody target in patients with alcoholic liver disease

The link between alcohol consumption and liver disease is not direct and several factors including autoimmunity to hepatocyte components have been implicated. We have previously identified alcohol dehydrogenase (ADH) as an autoantigen in autoimmune liver disease and in a proportion of patients with alcoholic liver disease. The aim of the present study is to investigate the association between the presence of anti-ADH antibodies, alcohol consumption and severity of liver damage in alcoholic patients. The presence of antibodies to human ADH beta2 and horse ADH was investigated in 108 patients with documented history of alcohol consumption and alcohol related liver disease, 86 being active alcohol abusers and 22 on sustained alcohol withdrawal, 39 with non-alcohol related disease and 22 normal subjects. Antibodies to either ADH form were more frequently detected in active alcohol abusers (55/86, 64%) than in patients on sustained alcohol withdrawal longer than 6 months (1/8, 13 %, P < 0.005), HBV infection (2/8, 25 %, P=0.03), non-alcohol related disease (9/29, 23 %, P < 0.0001) and in normal controls (3/22, 14 %, P < 0.0001); were more frequent in patients with cirrhosis than in those with steatosis (26/34, 76 % vs 34/64, 53 %, P=0.02); and were associated with elevated levels of ALT (anti-ADH beta2, P < 0.05), immunoglobulin A (P < 0.05) and gamma-glutamyl transpeptidase (P=0.01). Anti-ADH antibody positive serum samples were able to inhibit the enzymatic activity of ADH. These findings suggest that anti-ADH antibodies may be triggered by alcohol consumption and act as a disease activity marker in alcoholic liver disease.     

Effect of acute ethanol ingestion on integrated plasma prolactin levels in normal men

Healthy male subjects ingested 1.0 g ethanol/kg (Alcohol Day) and caloric equivalents of sucrose (Control Day). Plasma prolactin was determined on samples collected at 20-min intervals by serial constant blood exfusion, from 2 hr before to 4 hr after the drink. In 14 of the 15 men studied, plasma prolactin levels during the 2-hr period after alcohol administration were elevated an average of 31% above values for the preceding 2-hr period. Data pooled for all subjects revealed a small but statistically significant increase in prolactin coinciding with ascending and peak concentrations of blood alcohol. A significant increment in prolactin was associated with peak blood alcohol levels when values were compared between control and alcohol treatment days. Although of statistical significance, these transient and variable increases were within the normal range of basal prolactin levels for most subjects and are unlikely to be physiologically meaningful.     

Protective effects of saponins from the root of Platycodon grandiflorum against fatty liver in chronic ethanol feeding via the activation of AMP-dependent protein kinase

Fatty liver and steatosis induced by alcohol is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. However, the mechanism of liver injury and deposition of fatty liver due to alcohol is complex. The protective effects of saponins from the root of Platycodon grandiflorum (Changkil saponins: CKS) against ethanol-induced liver injury in an enteral alcohol feeding model was investigated. Male Sprague–Dawley rats were given control diets or ethanol-containing diets enterally for 4 weeks. Treatment with CKS for 2 weeks significantly prevented the alcohol-induced increase in serum alanine aminotransferase and aspartate aminotransferase activities or decrease in serum albumin levels. Alcohol elevated the hepatic triglyceride content and induced cytochrome P450 2E1 (CYP2E1) expression. CKS treatment reduced CYP2E1 expression and hepatic triglyceride accumulation and prevented alcoholic liver steatosis. Chronic alcohol feeding decreased AMP-activated protein kinase-alpha (AMPKα) phosphorylation, which was restored by CKS treatment. Recovery of AMPKα phosphorylation by CKS was also followed by an increase in acetyl-CoA carboxylase phosphorylation. Our study suggests that CKS is a promising agent for preventing or treating human alcoholic fatty liver disease.     

Hepatotoxic and neuroendocrine effects in physicians occupationally exposed to most modern halogenated anesthetics and nitrous oxide

The lack of data on hepatic and hormonal markers for occupational exposure to most modern halogenated anesthetics has stimulated our research, which assessed liver enzymes, high-sensitivity C-reactive protein (hs-CRP) and neuroendocrine response. The study investigated 106 physicians who were categorized in an exposed group (primarily exposed to isoflurane and sevoflurane and less to desflurane and nitrous oxide) as well as as a control group. Anesthetic air monitoring was performed, and biological samples were analyzed for the most important liver enzymes, hs-CRP, adrenocorticotrophic hormone, cortisol and prolactin. No biomarkers were significantly different between the groups. Exposed males showed significant increases in cortisol and prolactin compared to unexposed males. However, values were within the reference ranges, and 22 % of exposed males versus 5 % of unexposed males exhibited higher prolactin values above the reference range. This study suggests that occupational exposure to the most commonly used inhalational anesthetics is not associated with hepatotoxicity or neurohormonal changes.     

Impulsive-aggressive traits, serotonin function, and alcohol-enhanced aggression

Although alcohol consumption is involved in most acts of violence, most people do not become violent when they drink. Individuals also respond differently to alcohol on laboratory measures of aggression. The objective of this study was to determine whether individual differences in the effects of alcohol on a laboratory measure of aggression are related to specific personality traits and/or serotonin function, as measured by prolactin response to pharmacochallenge. Psychometric scales for impulsiveness, aggression, and anger, as well as a probe for suspiciousness, were administered to 10 healthy male social drinkers. Trait serotonin function was determined by citalopram challenge. The effect of alcohol on the Point Subtraction Aggression Paradigm was determined by comparing aggression scores with and without 1 g/kg alcohol. Impulsivity scores were significantly correlated with the change in aggressive responding after alcohol. Aggression, anger, and suspiciousness scores were not. Prolactin response did not predict the effect of alcohol on aggressive responding. The results suggest that trait impulsiveness may mediate the effects of alcohol on aggression in normal males.     

Alcohol effects on naloxone-stimulated luteinizing hormone, prolactin and estradiol in women

Plasma luteinizing hormone (LH), estradiol, prolactin and progesterone levels were measured in nine normal adult women prior to and following administration of naloxone and oral ingestion of ethanol or placebo-control solution. Each subject served as her own control in a double-blind study carried out during the midluteal phase of the menstrual cycle. The mean (+/- SD) progesterone level was 13.9 +/- 1.3 during control conditions and 13.9 +/- 1.7 during alcohol conditions. The mean peak blood alcohol level was 100 +/- 13 mg/dl within 45-60 min after initiation of drinking. Under placebo-control conditions, naloxone stimulated a significant increase in plasma LH and prolactin but did not increase estradiol or progesterone. Alcohol did not attenuate the significant naloxone stimulation of LH, and progesterone levels were equivalent under alcohol and control conditions. Alcohol significantly enhanced naloxone stimulation of prolactin and estradiol. Alcohol administration significantly augmented the naloxone-induced increase in plasma prolactin levels. After alcohol administration, naloxone also induced a significant increase in plasma estradiol levels, which was sustained throughout the 180-min sampling period. The mechanisms underlying alcohol's enhancement of naloxone-stimulated prolactin and estradiol remain to be determined. The alcohol-related increase in naloxone-stimulated prolactin secretion may reflect increased hypothalamic and/or pituitary sensitivity to alcohol following endogenous opioid blockade by naloxone or an effect of increased estrogen levels. The significant increase in plasma estradiol levels following concurrent naloxone and alcohol administration may occur as a consequence of alterations in steroid biotransformation associated with intrahepatic ethanol catabolism.     

Dopamine receptor responsivity in alcoholic patients before and after detoxification

OBJECTIVE: To assess central dopamine receptor responsivity in alcoholic patients during their usual alcohol consumption and after detoxification. METHOD: Plasma prolactin levels were measured at 0, 30, 60, and 90 min after administration of 5 mg haloperidol i.m. in 21 hospitalized male alcoholic patients during usual alcohol consumption, and 13 days later (mean, range 7-17 days), after detoxification. The test was also performed in seven healthy male volunteers. The patterns of prolactin responses were compared using repeated measures analysis of variance. RESULTS: The prolactin responses to haloperidol increased significantly after detoxification compared to those during usual alcohol consumption (state x time interaction P < 0.01; planned comparisons for times 0 and 90 min between states P = 0.03). Compared to controls, the responses of the patients before detoxification were lower (group-time interaction P = 0.001), and the difference was not significant after detoxification (P = 0.19). The magnitude of plasma prolactin (PRL) responses were not related to duration of alcohol abuse, score in the Brief Michigan Alcoholism Screening Test (BMAST) scale, or family history of alcoholism. CONCLUSIONS: Alcohol detoxification is accompanied by a normalization of the low responsivity of central dopaminergic receptors during alcohol abuse. The data support the hypothesis of a participation of the central dopaminergic system in alcohol dependence.     

Dexamethasone suppression test in alcohol withdrawal: relationship to depression and liver function.

The relationship between dexamethasone suppression test (DST) response, depressive symptoms and liver function tests was investigated in 15 male alcohol-dependent patients for 2 weeks during alcohol withdrawal. Six of the patients relapsed into drinking within the investigation period. There was no association between DST response and relapse, which suggests that abnormal DST response has no predictive value for relapse into drinking. About 50% of the patients had abnormal DST responses during the first week of alcohol withdrawal. There was no relationship between DST response and depression or depressive symptoms. Depression remitted within 1-2 weeks, whereas DST responses remained abnormal for at least 2 weeks in 2 of the non-relapsing 9 patients. Abnormal DST response in alcohol withdrawal is unlikely to be due to alterations in liver function but may be attributable to the effect of alcohol on the hypothalamic-pituitary-adrenocortical axis.     

Effect of grape (Vitis vinifera L.) leaf extract on alcohol induced oxidative stress in rats

Alcoholic liver disease is a major medical complication of drinking alcohol. Oxidative stress plays an important role in the development of alcohol liver disease. The present study was carried to evaluate the effect of grape leaf extract (GLEt) on antioxidant and lipid peroxidation states in liver and kidney alcohol induced toxicity. In vitro studies with DPPH* and ABTS*(+) (cation radical) showed that GLEt possesses antioxidant activity. In vivo administration of ethanol (7.9 g/kg bw/day) for 45 days resulted an activity of liver marker enzymes (AST, ALT, ALP and GGT), lipid peroxidation markers (TBARS, lipid hydroperoxides) in liver and kidney with significantly lower activity of SOD, CAT, GPx, GST and non-enzymatic antioxidants (vitamin E, vitamin C and GSH) in liver and kidney as compared with control rats. Administration of ethanol along with GLEt significantly decreased the activities of liver markers enzyme in serum towards near normal level. GLEt at a dose of 100 mg/kg was highly effective than 25 and 50 mg/kg body weight. In addition GLEt also significantly reduced the levels of lipid peroxidation and addition, significantly restored the enzymic and non-enzymatic antioxidants level in liver and kidney of alcohol administration rats. This observation was supplemented by histopathological examination in liver and kidney. Our data suggest that GLEt exerts its protective effect by decreased the lipid peroxidation and improving antioxidants status, thus proving itself as an effective antioxidant in alcohol induced oxidative damage in rats.     

Ethanol oxidizing enzyme activites in liver disease.

1 The activites of hepatic alcohol dehydrogenase, catalase and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent ethanol oxidizing system were determined in liver biopsies from nine patients with liver disease and seven control subjects with non evidence of liver disease. 2 Alcohol dehydrogenase and catalase activites were significantly lower in the patients with liver disease. 3 The activity of the NADPH dependent ethanol oxidizing system was significantly greater in the patients with liver disease, when its activity was expressed in terms of mg protein or g wet weight liver. 4 It is suggested that the greater activity of the NADPH dependent system may compensate for the low alcohol dehydrogenase activites found in patients with liver disease and maintain normal rates of ethanol metabolism.     

US Mortality from Liver Cirrhosis and Alcoholic Liver Disease in 1999–2004: Regional and State Variation in Relation to Per Capita Alcohol Consumption

Apparent per-capita alcohol consumption in 2001 in four US regions (West, Northeast, South, and Midwest), and in 50 states was examined in relation to mortality rates (1999–2004) from liver cirrhosis and for the subcategory alcoholic liver disease. Alcohol consumption and mortality rates were highest in the west. The alcoholic liver disease mortality rate by state was strongly correlated with alcohol consumption, but several outlier or mismatch states were identified. Per-capita alcohol consumption should be useful for US public health policy, as suggested for Europe and Canada, but outlier states require further study.     

U.S. mortality from liver cirrhosis and alcoholic liver disease in 1999-2004: regional and state variation in relation to per capita alcohol consumption

Apparent per-capita alcohol consumption in 2001 in four U.S. regions (West, Northeast, South, and Midwest), and in 50 states was examined in relation to mortality rates (1999-2004) from liver cirrhosis and for the subcategory alcoholic liver disease. Alcohol consumption and mortality rates were highest in the west. The alcoholic liver disease mortality rate by state was strongly correlated with alcohol consumption, but several outlier or mismatch states were identified. Per-capita alcohol consumption should be useful for US public health policy, as suggested for Europe and Canada, but outlier states require further study.     

Disposition of bupropion in healthy volunteers and subjects with alcoholic liver disease

Bupropion hydrochloride is a new monocyclic antidepressant. In humans, its disposition results in the formation of three major metabolites: the morpholinol metabolite, the erythroamino alcohol, and the threoamino alcohol metabolite. Bupropion's disposition was monitored following a single oral 200 mg dose in eight healthy volunteers and eight age- (44.5 +/- 8.4 years) and weight- (77.4 +/- 6.7 kg) matched volunteers with alcoholic liver disease. This latter group is of interest because the incidence of depression is more frequent in alcoholics than in the general population, and the liver is the major route of elimination for cyclic antidepressants. The mean elimination half-life of the morpholinol metabolite was significantly prolonged in subjects with alcoholic liver disease (32.2 +/- 13.5 vs. 21.1 +/- 4.9 hours (p less than 0.05), while the differences in bupropion (17.3 +/- 8.6 hours vs. 16.5 +/- 10.4 hours for healthy subjects and subjects with alcoholic liver disease, respectively), erythroamino alcohol (26.1 +/- 13.3 hours vs. 29.8 +/- 6.9 hours for healthy subjects and subjects with alcoholic liver disease, respectively), and threoamino alcohol (25.5 +/- 8.6 hours vs. 23.4 +/- 10.7 hours for healthy subjects and subjects with alcoholic liver disease, respectively) were minimal. Mean area under the plasma concentration time curves for bupropion and metabolites were increased in subjects with alcoholic liver disease; however, clear differences between means of these small groups did not emerge, probably due to the increased variability of bupropion pharmacokinetics in these subjects. As a therapeutic agent for the treatment of depression in chronic alcoholics who may consume alcohol in combination with their antidepressant therapy, the lack of sedation with bupropion could be advantageous.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanism-based PK–PD model for the prolactin biological system response following an acute dopamine inhibition challenge: quantitative extrapolation to humans

The aim of this investigation was to develop a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the biological system prolactin response following a dopamine inhibition challenge using remoxipride as a paradigm compound. After assessment of baseline variation in prolactin concentrations, the prolactin response of remoxipride was measured following (1) single intravenous doses of 4, 8 and 16?mg/kg and (2) following double dosing of 3.8?mg/kg with different time intervals. The mechanistic PK-PD model consisted of: (i) a PK model for remoxipride concentrations in brain extracellular fluid; (ii) a pool model incorporating prolactin synthesis, storage in lactotrophs, release into- and elimination from plasma; (iii) a positive feedback component interconnecting prolactin plasma concentrations and prolactin synthesis; and (iv) a dopamine antagonism component interconnecting remoxipride brain extracellular fluid concentrations and stimulation of prolactin release. The most important findings were that the free brain concentration drives the prolactin release into plasma and that the positive feedback on prolactin synthesis in the lactotrophs, in contrast to the negative feedback in the previous models on the PK-PD correlation of remoxipride. An external validation was performed using a dataset obtained in rats following intranasal administration of 4, 8, or 16?mg/kg remoxipride. Following simulation of human remoxipride brain extracellular fluid concentrations, pharmacodynamic extrapolation from rat to humans was performed, using allometric scaling in combination with independent information on the values of biological system specific parameters as prior knowledge. The PK-PD model successfully predicted the system prolactin response in humans, indicating that positive feedback on prolactin synthesis and allometric scaling thereof could be a new feature in describing complex homeostatic mechanisms.     

Serum prolactin correlates with depressed mood during alcohol withdrawal

Alterations in central dopamine function have been identified in depression and in alcohol withdrawal. Attempts to determine the magnitude and direction of the central dopamine alteration in alcohol withdrawal have produced conflicting results. In this study serum prolactin (PRL) was used as an indicator of central dopamine activity since dopamine is the most important factor in the control of prolactin secretion from the pituitary. Increased serum PRL levels were found during alcohol withdrawal and they correlated significantly with high scores on the Hamilton Depression Rating Scale (HDRS). No significant correlations were identified with The Brief Psychiatric Rating Scale (BPRS), the 'Mini-Mental State' of Folstein (MMS), The Beck Depression Inventory (BDI) or The Modified Gross Alcohol Withdrawal Selective Severity Assessment Scale (GAWSSA). The authors concluded that the transient depressive symptomatology typically found in detoxifying alcoholic patients may be, in part, the result of a central hypodopaminergic state.     

库普弗细胞在酒精性肝病发病机制中的作用研究进展

酒精性肝病（alcoholic liver disease,ALD）是由于酒精的过量摄入导致的肝脏损害及其一系列病变,给人类健康带来极大的威胁,是我国目前面临的一大医学问题。库普弗细胞（kupffercell,KC）是一种肝巨噬细胞,在ALD过程中能够在内毒素（LPS）、氧自由基等刺激下产生一些列细胞因子和炎症介质,介导肝细胞炎症反应,导致肝脏损伤。本文综述了国内外对于KC在ALD发病机制中的作用研究进展。