纳洛酮对酒精戒断致震颤谵妄患者疗效及安全性对照研究

目的:探讨纳洛酮对酒精戒断所致震颤谵妄的疗效及安全性。方法:将68例震颤谵妄患者随机分为纳洛酮组和地西泮组,各34例;两组在常规对症支持治疗基础上分别静脉滴注纳洛酮和或地西泮,疗程1周。采用酒精戒断状态评定量表(CIWA-Ar)评定疗效,治疗中出现的症状量表(TESS)评定不良反应。结果:纳洛酮组意识恢复时间[(63.3±22.0)h]明显短于地西泮组[(99.8±24.8)h](P0.001);CIWA-Ar评分在治疗后1~4 d明显低于地西泮组(P0.05或P0.01);不良反应中嗜睡出现率明显少于地西泮组(P0.05)。结论:纳洛酮与地西泮治疗酒精戒断所致震颤谵疗效相当,但纳洛酮起效快、不良反应少。     

Social stimuli augment estrogen receptor binding in preoptic area of female prairie voles

In female prairie voles ovarian estrogen secretion is stimulated by exposure to males. The present study determined that social stimuli can also enhance the neural response to estrogen. Ovariectomized female voles given a fixed amount of estradiol and exposed to males had higher levels of estrogen receptor binding in cell nuclei in the preoptic area than did females given estrogen and not exposed to males.     

Social isolation induces behavioral and neuroendocrine disturbances relevant to depression in female and male prairie voles

Supportive social interactions may be protective against stressors and certain mental and physical illness, while social isolation may be a powerful stressor. Prairie voles are socially monogamous rodents that model some of the behavioral and physiological traits displayed by humans, including sensitivity to social isolation. Neuroendocrine and behavioral parameters, selected for their relevance to stress and depression, were measured in adult female and male prairie voles following 4 weeks of social isolation versus paired housing. In Experiment 1, oxytocin-immunoreactive cell density was higher in the hypothalamic paraventricular nucleus (PVN) and plasma oxytocin was elevated in isolated females, but not in males. In Experiment 2, sucrose intake, used as an operational definition of hedonia, was reduced in both sexes following 4 weeks of isolation. Animals then received a resident-intruder test, and were sacrificed either 10 min later for the analysis of circulating hormones and peptides, or 2h later to examine neural activation, indexed by c-Fos expression in PVN cells immunoreactive for oxytocin or corticotropin-releasing factor (CRF). Compared to paired animals, plasma oxytocin, ACTH and corticosterone were elevated in isolated females and plasma oxytocin was elevated in isolated males, following the resident-intruder test. The proportion of cells double-labeled for c-Fos and oxytocin or c-Fos and CRF was elevated in isolated females, and the proportion of cells double-labeled for c-Fos and oxytocin was elevated in isolated males following this test. These findings suggest that social isolation induces behavioral and neuroendocrine responses relevant to depression in male and female prairie voles, although neuroendocrine responses in females may be especially sensitive to isolation.     

Inappropriate vasopressin secretion in severe alcohol withdrawal.

Forty-one male alcoholics suffering from alcohol withdrawal syndrome were investigated to assess the relationship between vasopressin (ADH), water homeostasis and alcohol withdrawal. During 10 d, we found a significant decrease in serum vasopressin, from 3.08 +/- 0.61 to 1.71 +/- 0.22 pg/nl. There were no concomitant changes in osmolality, so that a general dysregulatory state of vasopressin secretion during alcohol withdrawal cannot be assumed. Only patients with delirium tremens (8/41) had higher vasopressin levels despite lowered serum osmolalities. These findings support the hypothesis of an inappropriate rebound secretion of vasopressin in severe alcohol withdrawal. Furthermore, they may contribute to the pathogenesis of focal alcoholic brain damage, because rapid and/or profound changes in osmolality are suspected to cause circumscribed cerebral demyelinization.     

Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan

We have previously shown that coadministration of the dopamine (DA) agonist phentermine plus the serotonergic agonist fenfluramine suppresses alcohol intake and withdrawal seizures in rats. In the present study, phentermine and the serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (5-HTP), were administered alone, or in combination, to rats fed on a 6% alcohol-containing diet or an isocaloric control diet. Following a 9-h withdrawal period from the alcohol-containing diet, phentermine enhanced the effects of 5-HTP on both reduction of alcohol withdrawal seizures as well as changes in striatal serotonin. Food intake was monitored for 24 h after drug treatment, and neurochemical measures were examined at various time points. Phentermine alone reduced food intake in all diet conditions, but this anorectic effect was followed by hyperphagia in control rats. Phentermine plus 5-HTP reduced the consumption of the alcohol-containing diet, while its effects on consumption of control diets were mixed. In vivo microdialysis in rat nucleus accumbens revealed that phentermine increased extracellular DA, whereas 5-HTP caused marked elevations in extracellular 5-HT. Coadministration of phentermine and 5-HTP evoked simultaneous elevations in extracellular DA and 5-HT that mirrored the effects of each drug alone. Collectively, these findings show that coadministered phentermine plus 5-HTP is effective in reducing alcohol intake and suppressing alcohol withdrawal seizures. These therapeutic actions may be related to elevations in synaptic DA and 5-HT in critical brain regions.     

Treatment of alcohol withdrawal syndrome with a combination of tiapride/carbamazepine

This was a retrospective study to examine the efficacy, practicability and medical safety of a combination of tiapride and unretarded (fast acting formula) carbamazepine in the treatment of alcohol withdrawal syndrome. In five hospitals using this combination for treatment of alcohol withdrawal, 540 patients who had been treated with this combination were identified. An intensive evaluation of patients files and charts was performed. Details of alcohol history and comorbid disorders were extracted from patient files. Severity of alcohol withdrawal had been assessed using the CIWA-A-Score. Gender differences and differences between patients in their first and at least second withdrawal were computed by means of variance analyses (GLM). At baseline (day 1) mean dosage given was 796 for tiapride and 543 mg for carbamazepine. A pooled analysis of the results showed that, in general, medication was well tolerated. Withdrawal symptomatology as indicated by CIWA-A scores clearly decreased over time. Although a significant number of patients had a history of alcohol withdrawal delirium (103) and epileptic seizures (151), few patients suffered from them during treatment (8 and 5, respectively). Only 24 (4.4%) patients dropped out because of lack of efficacy or change of medication, 15 (2.8%) because of side effects. No case of malignant neuroleptic syndrome was recorded. Data analysis showed gender differences and differences between patients in their first and at least second withdrawal for side effects, complications, and in some CIWA-A-scores. In general, severe complications of withdrawal syndrome were more frequent in men compared to women and in patients with repeated inpatient treatment. In line with previous research, the results from this study give further evidence that a combination of the anticonvulsant carbamazepine and tiapride is an effective and safe treatment for alcohol withdrawal treatment.     

Photoperiodic and temporal influences on chemosensory induction of brain fos expression in female prairie voles

Prairie voles (Microtus ochrogaster) typically stop breeding during winter. Male prairie voles respond to winter day lengths with gonadal regression, whereas female voles are relatively unresponsive to photoperiod. Unlike commonly studied laboratory rodents, female prairie voles do not exhibit spontaneous oestrous cycles. Instead, females are induced into oestrus by chemosensory cues from conspecific male urine. The present study investigated the interaction among day length, chemosensory cues and the initial brain responses during oestrus induction in female voles. A single drop of male conspecific urine, saline or skimmed milk was applied to the nares of female prairie voles housed for 9 weeks in either long (LD 16 : 8 h) or short (LD 8 : 16 h) days. Animals were killed 0.5, 1, 2 or 24 h after chemosensory treatment and their brains were processed for Fos immunocytochemistry. Body mass and ovarian fat pad mass were higher, but uterine and ovarian mass were lower, in short-day compared to long-day females. Regardless of photoperiod, Fos- immunoreactivity increased in the granule layer of the accessory olfactory bulb (AOB), the supraoptic nucleus and bed nucleus of the stria terminalis (BNST) (anterior medial) in females treated with male urine compared to the two control groups. Fos staining intensified in the AOB, medial and posterocortical medial amygdala and BNST (posterior ventral), 1 h and 2 h after urine treatment. In the medial preoptic area, anterior and lateral hypothalamus, and ventromedial nucleus of the hypothalamus, Fos-immunoreactivity was elevated in females 2 h after receiving urine. Overall, long-day females displayed higher Fos expression in response to urine than females maintained in short days. These results identify a putative neural circuitry of oestrus induction in this species, and provide an approximate time line of activation in the brain circuit responsible for oestrus induction in prairie voles.     

Oxytocin selectively increases ERalpha mRNA in the neonatal hypothalamus and hippocampus of female prairie voles

During neonatal development exogenous oxytocin increases ERalpha immunoreactivity in the hypothalamus of female prairie voles. The purpose of this study was to determine if the increase in ERalpha is associated with an increase in ERalpha mRNA expression and to determine if the effect is specific to ER subtype or if oxytocin also influences ERbeta mRNA expression. On the day of birth female prairie vole pups were treated with oxytocin, an oxytocin antagonist, or saline. Brains were collected and RT-PCR was used to determine the effect of treatment on ER mRNA production in the hypothalamus, hippocampus, and cortex. Within 2h of treatment oxytocin significantly increased ERalpha mRNA expression in the hypothalamus and hippocampus, but not the cortex, while inhibiting the effects of endogenous oxytocin reduced the expression of ERalpha mRNA in the hippocampus. Neonatal treatment did not affect the expression of ERbetamRNA. The results demonstrate that the effects of oxytocin treatment are region and ER subtype specific and that during the neonatal period oxytocin can affect the expression of ERalpha by altering message production. The regional specific changes in ERalpha mRNA expression in females are consistent with studies examining the behavioral and physiological effects of neonatal manipulation of oxytocin in females.     

Social isolation alters central nervous system monoamine content in prairie voles following acute restraint

Animal models have shown that social isolation and other forms of social stress lead to depressive- and anxiety-relevant behaviors, as well as neuroendocrine and physiological dysfunction. The goal of this study was to investigate the effects of prior social isolation on neurotransmitter content following acute restraint in prairie voles. Animals were either paired with a same-sex sibling or isolated for 4 weeks. Plasma adrenal hormones and ex vivo tissue concentrations of monoamine neurotransmitters and their metabolites were measured following an acute restraint stressor in all animals. Isolated prairie voles displayed significantly increased circulating adrenocorticotropic hormone levels, as well as elevated serotonin and dopamine levels in the hypothalamus, and potentially decreased levels of serotonin in the frontal cortex. However, no group differences in monoamine levels were observed in the hippocampus or raphe. The results suggest that social stress may bias monoamine neurotransmission and stress hormone function to subsequent acute stressors, such as restraint. These findings improve our understanding of the neurobiological mechanisms underlying the consequences of social stress.     

Circadian rhythms of hormone concentrations in alcohol withdrawal

Abstract We investigated the circadian rhythm of hormones (Cortisol, melatonin) in alcoholic patients during and 1 month after alcohol withdrawal. Patients with delirium tremens had irregular serum hormone concentration rhythms during withdrawal, which normalized after the withdrawal period. Patients without delirium tremens had normal circadian rhythms even during the withdrawal period. We speculated that the disturbance of the biological oscillator, in terms of the decline of synchronizing function or the decrease in synchronizing factors, caused abnormal circadian rhythms of hormone release during delirium tremens.     

Central expression of c-Fos in neonatal male and female prairie voles in response to treatment with oxytocin

Early postnatal exposure to both exogenous and endogenous oxytocin (OT) can have long-term effects on behavior and physiology, although the mechanisms of these effects are not known. c-Fos expression was used to investigate the immediate neural effects of neonatal manipulations of OT in male and female prairie voles. On the day of birth prairie vole pups received an intraperitoneal injection of OT, a selective OT antagonist (OTA), or saline (vehicle control), while an additional group was handled but not injected. One hour after treatment brains were collected and fixed via spinning immersion and immunocytochemistry was then used to label for c-Fos immunoreactivity (IR). There were significant differences between males and females. Handled only females displayed significantly higher levels of c-Fos IR in the mediodorsal thalamic nucleus (MD) than males while handled males had higher c-Fos IR in the paraventricular nucleus of the hypothalamus than females. Exogenous OT stimulated neuronal activity in the supraoptic nucleus (SON) in males, while treatment with OTA increased Fos IR in the SON and was associated with reduced Fos IR in the MD in females. The results indicate that neuronal activity and responses to OT are sexually dimorphic in newborn prairie voles. In females changes in Fos expression were stimulated by treatment with OTA, suggesting that endogenous OT affects cellular activity while males responded to exogenous OT.     

Behavioral and cardiovascular consequences of disrupted oxytocin communication in cohabitating pairs of male and female prairie voles

ABSTRACT

Negative social experiences may influence psychological and physiological health via altered central oxytocin communication. The prairie vole is valuable for investigating the potential influence of oxytocin on responses to social experiences. Prairie voles are socially monogamous, live in pairs or family groups, and respond negatively to changes in the social environment. This study investigated the hypothesis that disruptions of oxytocin in one prairie vole of a cohabitating male-female pair would alter social behavior in that specific animal; and these behavioral changes in turn would influence the untreated partner’s behavior and physiology. Pharmacological antagonism of oxytocin with the receptor antagonist L-368,899 in the male prairie vole disrupted social behaviors between the male and his untreated female partner. This manipulation also negatively influenced the behavior and cardiovascular function in the untreated female partner, including increased: (a) depression-relevant behaviors in two behavioral stressors, (b) basal mean arterial pressure and heart rate, and (c) cardiovascular reactivity to the behavioral stressors. These results suggest that disruptions of oxytocin and social behavior in one animal may produce indicators of social stress in an untreated social partner. This preliminary research provides a foundation for future studies to investigate mechanisms underlying responses to social experiences in humans.     

Lesions of the vomeronasal organ disrupt mating-induced pair bonding in female prairie voles (Microtus ochrogaster)

The prairie vole (Microtus ochrogaster) is a highly social, monogamous species and displays pair bonding that can be assessed by the presence of selective affiliation with the familiar partner versus a conspecific stranger. In female prairie voles, exposure to a male or to male sensory cues is essential for estrus induction, and the subsequent mating facilitates pair bond formation. In the present study, we examined the role of the vomeronasal organ (VNO) in estrus induction and pair bonding in female prairie voles. VNO lesions did not alter olfaction mediated by the main olfactory system, but did prevent male-induced estrus induction. We by-passed the necessity of the VNO for estrus induction by estrogen priming the females. Despite the fact that all subjects displayed similar levels of mating, social contact and locomotor activities, VNO lesioned females failed to show mating-induced pair bonding whereas intact and sham-lesioned females displayed a robust preference for the familiar partner. Our data not only support previous findings that the VNO is important for estrus induction but also indicate that this structure is crucial for mating-induced pair bonding, suggesting an important role for the VNO in reproductive success in prairie voles.     

Progesterone attenuates persistent inflammatory hyperalgesia in female rats: involvement of spinal NMDA receptor mechanisms

The relationship between endogenous gonadal steroid levels and persistent or chronic pain is poorly understood. These studies used an inflammation model to examine the role of the gonadal steroid, progesterone, in the development of persistent pain and hyperalgesia in lactating ovary-intact and ovariectomized rats. The results indicate that constant high plasma levels of progesterone attenuate inflammatory hyperalgesia by a mechanism involving inhibition of N-methyl-D-aspartate receptor activation at the spinal cord level. Since the pattern of high progesterone in lactating rats mimics the progesterone component of the luteal phase of the human menstrual cycle, these findings have significance in persistent or chronic pain conditions that are most prevalent in females.     

Dopamine and N-methyl-D-aspartate receptor expression in peripheral blood of patients undergoing alcohol withdrawal

Summary The aim of the present pilot study was to explore whether a change in cerebral receptors can be demonstrated in human peripheral blood lymphocytes during alcohol withdrawal. Dopamine (D1 and D2) and NMDA (1 and 2B) receptor expressions of 14 male patients suffering from alcohol-dependency were assessed through quantitative RT-PCR. A significant difference in D1 receptor expression (T = 2.361; p = 0.035) in terms of up-regulation could be shown, though there were no significant changes concerning D2, NMDA1 or NMDA2B receptor expression. First two authors contributed equally     

Social inequality and alcohol consumption-abuse in Bahia, Brazil

Abstract Background This paper reports findings on Alcohol Consumption-Abuse (ACAb) in Bahia, Brazil, a research setting characterized by racial/ethnic and socioeconomic diversity. Methods A household survey was conducted with a sample of 2,302 adults. ACAb was defined as daily intake of more than two units of beverage, with drunkenness, or weekly binge drinking plus episodes of drunkenness, or any use of alcoholic beverages with frequent drunkenness, with failed attempts to stop drinking. Results The rate of 12-month prevalence was 7%, with an overall male: female ratio of 6:1. A positive association of ACAb prevalence with education and social class was found. Male gender and higher socio-economic status were associated with increased odds of ACAb. No relationship was found between ethnicity and ACAb. Stratified analysis yielded consistent gender effects, throughout all strata of independent variables. A strong interaction of gender (male) and social class (upper class) was found for Mulattos and Morenos (maximum Prevalence rate = 9.04). Conclusion Interaction patterns found defy simple generalizations based on class, ethnicity, and gender considered alone.     

Expression and estrogen regulation of brain-derived neurotrophic factor gene and protein in the forebrain of female prairie voles

Brain-derived neurotrophic factor (BDNF) has been linked to the development, differentiation, and plasticity of the central nervous system. In the present study, we first used a highly specific affinity-purified antibody and a cRNA probe to generate a detailed mapping of BDNF immunoreactive (BDNF-ir) staining and mRNA labeling throughout the forebrain of female prairie voles. Our data revealed that (1) BDNF-ir cells were present essentially in the brain regions in which BDNF mRNA-labeled cells were found; (2) BDNF-ir fibers were distributed extensively throughout many forebrain regions; and (3) BDNF mRNA was also detected in some thalamic regions in which BDNF-ir fibers, but not immunostained cells, were present. With few exceptions, the distribution pattern of BDNF in the vole brain generally resembled the pattern found in rats. In a second experiment, we examined the effects of estrogen on BDNF expression. Ovariectomized prairie voles that were treated with estradiol benzoate had a higher level of BDNF mRNA labeling in the dentate gyrus and CA3 region of the hippocampus, as well as in the basolateral nucleus of the amygdala, than did ovariectomized voles that were treated with vehicle. In addition, estrogen treatment increased the density of BDNF-ir fibers in the lateral septum, dorsolateral area of the bed nucleus of the stria terminalis, and lateral habenular nucleus. These data suggest that estrogen may regulate BDNF at the level of gene and protein expression, and thus, BDNF may be in a position to mediate the effects of estrogen on the brain of the prairie vole.     

Social cognition and social problem solving abilities in individuals with alcohol use disorder

Background: Up to now, little is known about higher order cognitive abilities like social cognition and social problem solving abilities in alcohol-dependent patients. However, impairments in these domains lead to an increased probability for relapse and are thus highly relevant in treatment contexts. Method: This cross-sectional study assessed distinct aspects of social cognition and social problem solving in 31 hospitalized patients with alcohol use disorder (AUD) and 30 matched healthy controls (HC). Three ecologically valid scenario-based tests were used to gauge the ability to infer the mental state of story characters in complicated interpersonal situations, the capacity to select the best problem solving strategy among other less optimal alternatives, and the ability to freely generate appropriate strategies to handle difficult interpersonal conflicts. Standardized tests were used to assess executive function, attention, trait empathy, and memory, and correlations were computed between measures of executive function, attention, trait empathy, and tests of social problem solving. Results: AUD patients generated significantly fewer socially sensitive and practically effective solutions for problematic interpersonal situations than the HC group. Furthermore, patients performed significantly worse when asked to select the best alternative among a list of presented alternatives for scenarios containing sarcastic remarks and had significantly more problems to interpret sarcastic remarks in difficult interpersonal situations.

Conclusions: These specific patterns of impairments should be considered in treatment programs addressing impaired social skills in individuals with AUD.     

The influence of the semax nootropic agent on the behavioral signs of the withdrawal syndrome and on the craving for alcohol in white rats and the determination of its clinical efficacy and safety in patients with alcohol dependence

The influence of a course of medical treatment with the Semax nootropic peptide (50 and 200 μg/kg) on alcohol motivation and general behavior was studied in rats preliminarily alcoholized over six months. Semax was also included in the scheme of complex therapy of human alcohol dependence in clinical practice. Experiments with rats showed an increase in the locomotor and exploratory activity of rats and a decrease in the degree of depressive-like components. This effect compensated the behavioral changes observed in the control group exposed to alcohol deprivation. At the same time, the behavior of test groups under anxiogenic conditions showed increased anxiety. Semax in a dose of 200 μg/kg caused a significant increase in alcohol motivation, whereas its lower dose induced no proalcohol effect. Clinical trials demonstrated the safety (the absence of side effects and fairly high tolerance) of Semax in the course of alleviating the acute withdrawal syndrome and its efficacy for the recovery of mnestic functions (which was similar to the efficacy of Pyracetam). Semax did not change the frequency of cases of pathological craving for alcohol, but increased the overall intensity of behavioral reactions, which made the craving for alcohol stronger. These results allowed determination of safe course doses of Semax (to 50 μg/kg) under conditions of chronic alcoholization and inclusion of this nootropic agent in a scheme of complex therapy for patients with alcohol dependence. The mechanisms underlying the individual differences in the effects of Semax should be studied further. Original Russian Text ? M.L. Lovat’, M.A. Vinnikova, N.A. Kozyreva, E.A. Kushnir, R.D. Platonova, I.P. Ashmarin, 2008, published in Neirokhimiya, 2008, Vol. 25, Nos. 1–2, pp. 49–56