Effects of chronic alcohol consumption,withdrawal and nerve growth factor on neuropeptide Y expression and cholinergic innervation of the rat dentate hilus

Several studies have demonstrated the vulnerability of the hippocampal formation (HF) to chronic alcohol consumption and withdrawal. Among the brain systems that appear to be particularly vulnerable to the effects of these conditions are the neuropeptide Y (NPY)-ergic and the cholinergic systems. Because these two systems seem to closely interact in the HF, we sought to study the effects of chronic alcohol consumption (6 months) and subsequent withdrawal (2 months) on the expression of NPY and on the cholinergic innervation of the rat dentate hilus. As such, we have estimated the areal density and the somatic volume of NPY-immunoreactive neurons, and the density of the cholinergic varicosities. In addition, because alcohol consumption and withdrawal are associated with impaired nerve growth factor (NGF) trophic support and the administration of exogenous NGF alters the effects of those conditions on various cholinergic markers, we have also estimated the same morphological parameters in withdrawn rats infused intracerebroventricularly with NGF. NPY expression increased after withdrawal and returned to control values after NGF treatment. Conversely, the somatic volume of these neurons did not differ among all groups. On other hand, the expression of vesicular acetylcholine transporter (VAChT) was reduced by 24% in ethanol-treated rats and by 46% in withdrawn rats. The administration of NGF to withdrawn rats increased the VAChT expression to values above control levels. These results show that the effects of prolonged alcohol intake and protracted withdrawal on the hilar NPY expression differ from those induced by shorter exposures to ethanol and by abrupt withdrawal. They also suggest that the normalizing effect of NGF on NPY expression might rely on the NGF-induced improvement of cholinergic neurotransmission in the dentate hilus.     

The benzodiazepine/GABA receptor complex during severe ethanol intoxication and withdrawal in the rat

The benzodiazepine/GABA (gammaaminobutyric acid) receptor complex was investigated during severe ethanol intoxication and withdrawal in the rat. The intragastric intubation technique was used to establish physical ethanol dependence in the animals. Cerebral cortex from male Wistar rats was studied 1) after 3 1/2 days of severe ethanol intoxication, 2) during the ethanol withdrawal reaction and 3) in a control group. The effect of GABA-ergic activation by muscimol and THIP (4,5,6,7-tetrahydroisoxazole(5,4-c)pyridin-3-01) on ³H-diazepam binding was unchanged during ethanol intoxication and withdrawal, as was the affinity constant (K_D) and the maximal number of binding sites (B_max) for ³H-flunitrazepam. In conclusion, the benzodiazepine/GABA receptor complex is unlikely to play any causal part in physical ethanol dependence.     

Nitric oxide mediates cardiovascular symptoms in alcohol withdrawal

We studied whether nitric oxide is involved in cardiovascular symptoms in alcohol withdrawal. Cardiovascular effects of isosorbide dinitrate (ISDN; 20 mg sublingually), a nitric oxide donor were compared in 21 alcohol-dependent subjects during alcohol withdrawal (n=11) on days 1, 2, 3, and 10 to those during remission (n=10; duration=60.7+/-10.5 days). Cardiovascular parameters were measured non-invasively. The levels of systolic and diastolic blood pressure, total peripheral resistance were significantly higher in patients with withdrawal than in remission. Same cardiovascular parameters showed different response to ISDN during withdrawal when compared to remission. The differences were largest during the initial phase (1-2 days) of withdrawal. Nitric oxide may mediate at least some cardiovascular symptoms in withdrawal.     

Elevated prolactin serum levels and history of alcohol withdrawal seizures

BACKGROUND: Prolactin has been discussed to be useful for differential diagnosis in epilepsia. Aim of the present study was to investigate the association between prolactin serum levels and previous alcohol withdrawal seizures. METHODS: We assessed 118 male patients admitted for detoxification treatment. Previous withdrawal seizures were recorded and prolactin serum levels were measured using an enzymatic immunoassay. RESULTS: Patients with a history of alcohol withdrawal seizures had significantly higher prolactin levels (17.8 ng/ml, SD=12.1) than patients without previous seizures (13.0 ng/ml, SD=8.1, p<0.05). Logistic regression revealed significant predictive qualities for prolactin serum levels (B=0.05, Wald=5.30, p=0.021, OR=1.06, 95%CI=1.01-1.11). CONCLUSIONS: The present findings show an association between elevated prolactin serum levels and a history of withdrawal seizures. Hence, the results suggest that prolactin elevation at admission may be a clinical marker for an increased risk of withdrawal seizures.     

Raised plasma nerve growth factor levels associated with early-stage romantic love

Our current knowledge of the neurobiology of romantic love remains scanty. In view of the complexity of a sentiment like love, it would not be surprising that a diversity of biochemical mechanisms could be involved in the mood changes of the initial stage of a romance. In the present study, we have examined whether the early romantic phase of a loving relationship could be associated with alterations in circulating levels of neurotrophins (NTs). Plasma levels of NGF, BDNF, NT-3 and NT-4 were measured in a total of 58 subjects who had recently fallen in love and compared with those of two control groups, consisting of subjects who were either single or were already engaged in a long-lasting relationship. NGF level was significantly higher (p < 0.001) in the subjects in love [mean (SEM): 227 (14) pg/ml] than in either the subjects with a long-lasting relationship [123 (10) pg/ml] or the subjects with no relationship [149 (12) pg/ml]. Notably, there was also a significant positive correlation between levels of NGF and the intensity of romantic love as assessed with the passionate love scale (r = 0.34; p = 0.007). No differences in the concentrations of other NTs were detected. In 39 subjects in love who-after 12-24 months-maintained the same relationship but were no longer in the same mental state to which they had referred during the initial evaluation, plasma NGF levels decreased and became indistinguishable from those of the control groups. Taken together, these findings suggest that some behavioural and/or psychological features associated with falling in love could be related to raised NGF levels in the bloodstream.     

Apolipoprotein E gene polymorphism and previous alcohol withdrawal seizures

Aim of this study was to investigate the possible association of apolipoprotein E (ApoE) gene polymorphism with a history of alcohol withdrawal seizures. We included 194 patients with alcohol dependence who were divided into patients with (SZ+) and without (SZ-) previous alcohol withdrawal seizures. ApoE genotypes were determined using PCR. For statistical analysis we examined the number of ApoE alleles (ApoE2: n=36; ApoE3: n=311; ApoE4: n=41). A significant positive association with a positive history of withdrawal seizures (SZ+) was found in the ApoE3 allele group (Fisher's exact test: p=0.006) while a significant negative association was observed in the ApoE2 allele group (Fisher's exact test: p=0.029). For the ApoE4 allele group no significant differences were found regarding a history of withdrawal seizures. Our findings suggest an association between the apolipoprotein E3 gene variant and an elevated risk of alcohol withdrawal seizures. These preliminary results must be validated in further studies.     

Chronic treatment with scopolamine and physostigmine changes nerve growth factor (NGF) receptor density and NGF content in rat brain

Nerve growth factor (NGF) and NGF receptors were measured in cortex and hippocampus of rats treated with drugs affecting cholinergic neurotransmission. High (K_d= 0.045nM) and low (K_d= 21nM) affinity¹²⁵I-NGF binding sites were present in both cortical and hippocampal membranes with hippocampus containing higher numbers of both sites than cortex. Chronic treatment of rats with the muscarinic receptor antagonist scopolamine (5 mg/kg, twice daily) decreased the density of high- and low-affinity sites by 50–90% in cortical and hippocampal membranes. These changes were seen after 7 days, but not 3 days, of scopolamine treatment. Chronic infusion of physostigmine (1 mg/kg/day) using minipumps increased the number of high- and low-affinity sites in cortex 3- and 6-fold, respectively. The changes in receptor-binding parameters induced by physostigmine were transient as they were evident after 3 days of treatment, but returned to control levels after 7 days. NGF content in cortex and hippocampus was reduced by about 50% following 7, but not 3, days of chronic physostigmine infusion. In contrast, scopolamine treatment failed to change NGF levels in the cholinergic neuronal target regions but it decreased NGF content in the septal area. The content of NGF mRNA in the cortex measured by Northern blot analysis failed to change following either scopolamine or physostigmine treatment. The results suggest that levels of NGF and NGF receptors in the target regions of cholinergic neurons are regulated by the extent of cholinergic neurotransmitter activity.     

Parkinsonism in alcohol withdrawal: case report and review of the literature

A case of severe, acute parkinsonism occurring in a 60-year-old man after cessation of chronic alcohol consumption, is reported. He recovered completely in 3 months without specific therapy. The literature on alcohol withdrawal parkinsonism including nine other cases, is reviewed.     

Electrolyte changes and acid base balance after alcohol withdrawal

70 chronic alcoholics in the withdrawal state, 45 with convulsions and 25 controls without convulsive seizures, were tested with respect to electrolyte changes and acid base balance in serum or blood and cerebrospinal fluid (CSF). It was of special interest to note that there was a partial independence between magnesium levels in serum and CSF. Thus the serum level has only a limited liability as to magnesium depletion suggested to be responsible for seizure precipitation. In the seizure group a slightly but significantly lower magnesium, potassium and calcium in CSF and a significant decrease of potassium and calcium in serum were revealed. In the nonzeizure controls a similar decrease of magnesium in serum and potassium in CSF was observed while serum potassium and calcium in CSF and serum remained in low normal range. In both groups there was a prominent respiratory alkalosis. The role of magnesium depression for seizure precipitation is discussed with respect to the concomitant changes of other electrolytes and acid base disturbances.     

Serum withdrawal causes apoptosis in SHSY 5Y cells

A proportion of differentiated SH-SY5Y cells undergo cell death in response to withdrawal of serum. This death manifests the hallmark features of apoptosis including changes in nuclear morphology, processing and activation of caspase 3 and cleavage of the caspase 3 substrates acetyl-Asp-Glu-Val-Asp-aminomethylcoumarin and poly(ADP-ribose) polymerase. These findings represent the first demonstration of serum withdrawal induced apoptosis in SH-SY5Y cells. The reduction in viability induced by serum deprivation and assessed using an inhibitor of mitochondrial respiration can be partially inhibited by FK506, but FK506 does not prevent caspase 3 processing or cleavage of caspase 3 substrates. FK506 is also able to promote the viability of a small proportion of embryonic mouse sensory neurons following nerve growth factor-withdrawal induced apoptosis. FK506 did not promote viability in either cell type in the absence of serum- or nerve growth factor-withdrawal. These observations are consistent with a survival-promoting effect of FK506 in cultured neurons.     

脑出血患者血清肝细胞生长因子神经生长因子水平与神经功能缺损的相关性

目的 分析脑出血患者肝细胞生长因子(HGF)、神经生长因子(NGF)水平与神经功能缺损的相关性.方法 选取濮阳市安阳地区医院2018-01—2020-01收治的237例脑出血患者为研究对象,均于入院时检测HGF及NGF水平,于发病72 h时评估神经功能缺损程度,分析HGF和NGF水平与患者神经功能缺损的相关性.结果 2...     

Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism

Summary. Higher plasma homocysteine levels have been found in actively drinking alcoholics as well as in early abstinent patients. Furthermore, elevated homocysteine levels are associated with cognitive decline in dementia and in healthy elderly people. The aim of this prospective study was to investigate a possible association between homocysteine serum levels and clinically well known cognitive deficits during alcohol withdrawal. We examined 89 patients (67 men, 22 women) during early withdrawal treatment. Cognitive function was assessed using the c.I.-Test. Patients with cognitive deficits showed significantly higher homocysteine serum levels (Mann-Whitney-U, p = 0.004) than patients without cognitive deficits, while the difference in blood alcohol concentration was not significant. Using logistic regression analysis, cognitive deficits were best predicted by high homocysteine serum levels (Wald χ² = 4.071, OR = 1.043, 95% CI 1.001–1.086, p<0.05), which was confirmed by Receiver Operating Curves (AUC = 0.68, 95% CI = 0.57–0.79, p = 0.004). The present results show first evidence of an association between elevated plasma homocysteine levels in alcoholics and cognition deficits in patients undergoing alcohol withdrawal.     

丙戊酸钠与地西泮治疗酒清戒断反应的临床对照研究

目的探讨丙戊酸钠对酒精戒断反应的临床疗效及副反应.方法对61例慢性酒精中毒患者应用丙戊酸钠(31例)与地西泮(30例)进行对照治疗,疗程1周,采用戒断症状量表、汉密尔顿焦虑量表(HAMA)和有关实验室等检查评定疗效和副反应.结果丙戊酸钠与地西泮疗效相近(P＞0.05).治疗前后戒断症状量表、HAMA量表总分减分率两组均有显著性差异.HAMA的精神性焦虑因子减分率丙戊酸钠组大于地西泮组(P＜0.05).两组副反应均很少且轻微.结论丙戊酸钠与地西泮对酒精戒断反应均有良好疗效,但丙戊酸钠一般不会造成滥用和成瘾.     

Chronic alcohol intoxication in rats leads to a strong but transient increase in NGF levels in distinct brain regions

Summary. Nerve growth factor (NGF), a member of the neurotrophin family, is an essential mediator of neuronal activity and synaptic plasticity of basal forebrain cholinergic neurons. In this study NGF-protein levels were determined in areas of the basal forebrain cholinergic system, its projection areas as well as the striatum and the cerebellum after long-term exposure (6 and 9 months) to ethanol and a phase of withdrawal in male Sprague-Dawley rats. 6-month alcohol treatment led to an increase of NGF to 650–850% of controls in the basal forebrain and the septum and to a 210–485% increase in the cholinergic projection areas (anterior cortex, hippocampus and olfactory bulb). After 9 months exposure to ethanol, a decrease of NGF by 16% in the frontal cortex was observed compared to controls. In the other brain regions no differences in NGF expression were detectable at this time-point. These results support the idea of an endogenous neuroprotective mechanism acting through a transient NGF induction followed by a decrease in NGF-levels during the course of further neuronal degeneration. Authors contributed equally to this study     

A double-blind comparison of carbamazepine and clomethiazole in the treatment of alcohol withdrawal syndrome

The efficacy and tolerability of carbamazepine and clomethiazole in the treatment of alcohol withdrawal symptoms were compared in a double-blind study with 68 hospitalized patients. Target withdrawal symptoms, the patient's subjective feeling and unwanted effects were recorded daily during the 1 week-treatment period. No significant differences between the two treatments could be demonstrated in the parameters studied. It appears that carbamazepine, which is widely used as an antiepileptic drug, well tolerated and not likely to produce any addiction as such, might offer a valuable alternative treatment for the symptoms of alcohol withdrawal.     

男性酒依赖患者食欲素A与急性期戒断反应的相关性

目的探讨男性酒依赖患者血浆食欲素A(orexin-A,OXA)浓度与急性期酒精戒断反应、心理渴求之间的关系。方法纳入60例男性酒依赖患者和60名健康成年男性。收集一般人口学资料,检测血浆OXA浓度,以及总胆固醇、肌酸激酶、谷丙转氨酶、谷草转氨酶、血糖及血钾水平,使用修订版临床酒精戒断症状评估量表中文版(clinic institute alcohol withdrawal syndrome scale,CIWA-Ar)及视觉模拟量表(visual analogues scale,VAS)评估患者酒精戒断反应严重程度和心理渴求程度;患者组接受戒酒治疗14 d后,再次检测OXA及血生化指标,以及评估CIWA-Ar及VAS。结果入组时患者组血浆OXA、总胆固醇、肌酸激酶、谷丙转氨酶、谷草转氨酶及血糖水平高于对照组(均P<0.05),血钾浓度低于对照组(P<0.05)。在入组时患者组中轻度戒断反应者血浆OXA水平低于中度或重度戒断反应者(均P<0.05)。患者组治疗前后血浆OXA浓度、CIWA-Ar评分、VAS得分存在统计学差异(均P<0.05)。患者入组时血浆OXA的水平与CIWA-Ar评分(r=0.34,P<0.01)和VAS评分(r=0.47,P<0.01)均具有统计学相关性。结论在急性酒精戒断期男性酒依赖患者血浆OXA水平可能与戒断反应、渴求有关。     

Barbital and diazepam plasma levels during treatment of delirium tremens.

Plasma concentrations of barbital and diazepam were measured daily during a double-blind study of the efficacy of the two drugs in the treatment of delirium tremens and less severe clinical states. Treatment was estimated as satisfactory in the majority of cases; the present study deals with the satisfactory groups only. Both in the barbital group and in the diazepam group the same plasma level was seen in different clinical states. This result is discussed in relation to the theories about the aetiology of delirium tremens, and it is concluded that the data fits best with the assumption that delirium tremens is released from a withdrawal state, but once established, the delirious state is not interrupted by the drugs. The barbital concentrations were rather high, many at a level where non-alcoholics would show pronounced intoxication symptoms not seen in the present material. The diazepam concentrations on the other hand were low, often below a level where a cerebral effect is measurable in normal subjects. On this basis it is concluded, that the two drugs have different modes of action. Barbital may act by its cross-dependence properties with alcohol and thus diminish the withdrawal reaction, whereas diazepam may act by its anti-anxiety effect, but not in the doses here applied, by cross-dependence properties with alcohol. Finally, this hypothesis is discussed in relation to clinical experience in the treatment of delirium tremens.     

奎硫平对酒依赖患者稽延性戒断症状及睡眠的影响

目的:评估奎硫平对酒依赖患者稽延性戒断症状的治疗效果及睡眠质量和睡眠结构的影响。方法:选取80例酒依赖患者急性期戒酒治疗后随机分为奎硫平治疗组(研究组)和维生素治疗组(对照组),研究组给予200~400 mg/d奎硫平治疗,对照组给予维生素治疗。采用宾西法尼亚酒精渴求量表(PACS)、视觉模拟渴求量表(VAS)及汉密尔顿抑郁量表(HAMD)、汉密尔顿焦虑量表(HAMA)分别于入组时和治疗4周对两组患者进行评定,同时接受多导睡眠图(PSG)检测。结果:治疗前两组PACS、VAS和HAMD、HAMA评分差异无统计学意义(P0.05),治疗后研究组PACS、VAS和HAMD、HAMA总分较治疗前均显著降低,差异有统计学意义(P0.05)。治疗前两组PSG各指标差异无统计学意义(P0.05),治疗后研究组觉醒次数(AN)减少[(5.93±1.53)vs(6.91±1.60),t=2.559,P=0.000],睡眠效率(SE)升高[(68.3±4.17)vs(60.8±4.20),t=7.316,P=0.000],总睡眠时间(TST)增加[(292.5±25.9)vs(271.7±23.3),t=3.451,P=0.018],差异有统计学意义。睡眠潜伏期(SL)、快眼动睡眠(REM)百分比及REM睡眠潜伏期(RL)等指标两组间差异无统计学意义(P0.05)。对照组治疗前后各指标差异无统计学意义(P0.05)。结论:奎硫平可改善酒依赖患者急性戒断后的心理渴求、焦虑、抑郁等稽延性戒断症状,提高部分睡眠质量。     

Twenty-four hour ambulatory monitoring of tremor,sweating, skin temperature and locomotor activity in the alcohol withdrawal syndrome

An ambulatory monitor has been used to determine the characteristic patterns of tremor, sweating, skin temperature and locomotor activity in subjects undergoing alcohol withdrawal. Twenty-four hour records were obtained from six male subjects who had been consuming an average of 345 g of alcohol per day prior to cessation and from a group of agematched controls. Consistent with earlier research and clinical observation, tremor, sweating and locomotor activity were elevated in withdrawal subjects. Sweating was greatest in the period from approximately 00.00 h to 06.00 h, as was skin temperature. Tremor and activity levels decreased during this period, but were considerably higher in withdrawal subjects. The data suggest that 24-h monitoring of alcohol withdrawal using objective methods provides a more sensitive assessment technique than the standard clinical approaches. The technique may be of value in other dysautonomic states.