Differential effects of withdrawal from chronic amphetamine or fluoxetine administration on brain stimulation reward in the rat – interactions between the two drugs

Rationale: Withdrawal from chronic amphetamine administration is characterized by deficits in reward that resemble some symptoms of depression. Nevertheless, the effects of long-term administration and withdrawal from other drugs, such as fluoxetine, that have the potential to elevate mood in depressed individuals have not been characterized. Objectives: The purpose of this study was to characterize the effects of withdrawal from chronic amphetamine or fluoxetine administration on central reward function. Furthermore, the effects of acute or chronic pretreatment with fluoxetine on responsiveness to an acute amphetamine challenge were examined to identify potential interactions between the two drugs. Methods: A rate-independent discrete-trial threshold procedure was used to characterize self-stimulation behavior in rats prepared with bipolar electrodes in the medial forebrain bundle. Results: Elevations in intracranial self-stimulation (ICSS) thresholds, reflecting a decrease in the reward value of the stimulation, were associated with withdrawal from various chronic amphetamine treatment regimens (1–5 mg/kg, three injections per day for 1, 2, 4 or 6 days). The magnitude and duration of threshold elevations were proportional to the duration and dose of amphetamine treatment prior to withdrawal. In contrast, no alterations in ICSS thresholds were associated with withdrawal from chronic fluoxetine treatment (5 mg/kg/day for 15 days). While neither acute nor chronic administration of fluoxetine alone altered ICSS thresholds, chronic pretreatment with fluoxetine blocked the threshold-lowering effect of acute amphetamine administration (4 mg/kg), but acute pretreatment did not. Amphetamine-induced decreases in response latency, a measure of motor performance, were not affected by either chronic or acute fluoxetine pretreatment. Conclusions: The results of these experiments suggest that chronic fluoxetine treatment may induce adaptive changes in serotonergic transmission that, in themselves, do not alter the function of central reward processes, but may alter the ability of amphetamine to potentiate ICSS reward. In addition, the lack of change in ICSS thresholds during withdrawal from the chronic fluoxetine treatment regimen used suggests that withdrawal from all mood-altering drugs may not necessarily produce changes in central reward functions. Received: 10 September 1998 / Final version: 8 March 1999     

Resistance to hypoglycemia of cerebellar transplants in the rat forebrain

Summary Prolonged insulin-induced hypoglycemia causes widespread loss of neurons and permanent brain damage with irreversible coma. Although the deprivation of carbohydrate stores affects all brain regions, the breakdown of energy metabolism and cessation of protein synthesis occur predominantly in the cerebral cortex, caudoputamen and hippocampus. The cerebellum, brain stem and hypothalamus are largely resistant. Following transplantation of the cerebellar anlage of rat fetuses (day 15 of gestation) into the caudoputamen of adult rats, the grafts were allowed to differentiate for a period of 8 weeks. The host animals were then subjected to 30 min of severe hypoglycemia with isoelectric EEG (coma). In contrast to the surrounding vulnerable brain structures, protein synthesis was fully preserved within the cerebellar transplant. Grafting of fetal forebrain cortex to the same location did not result in escape from hypoglycemic cell injury. This indicates that resistance to hypoglycemia is part of the programmed differentiation of the cerebellum and develops irrespective of its location and functional integration within the nervous system.Dedicated to Prof. F. Seitelberger on the occasion of his seventieth birthdaySupported by the Deutsche Forschungsgemeinschaft (SFB 70)     

Identification and quantitative determination of mercapturic acids formed from Z- and E-1,3-dichloropropene by the rat,using gas chromatography with three different detection techniques

Z- and E-1,3-dichloropropene, mutagenic geometric isomers and major constituents of commercial soil fumigants, were found to be metabolized to mercapturic acid derivatives by the rat. Extremely small quantities of mixtures of the parent compounds were administered intraperitoneally to the rat and the isomeric urinary mercapturic acids were quantified in three ways. Gas chromatographic procedures with nitrogen selective, sulphur selective and mass spectrometric detection, using negative chemical ionization with single ion detection, were evaluated with respect to selectivity and sensitivity. Applying the former two techniques, urinary mercapturic acids could still be quantified following 5 g doses of each of the dichloropropene isomers. With gas chromatography-negative chemical ionization mass spectrometry, only mercapturic acid metabolites arising from 25 g doses and higher could be quantified because of interference from endogenous compounds. These results suggest that all three analytical methods can be used to determine exposure of men to soil fumigants containing low levels of 1,3-dichloropropene.Abbreviations MA mercapturic acid - MAME mercapturic acid methyl ester - DCP 1,3-dichloropropene - SID single ion detection - GC-MS gas chromatography — mass spectrometry - GC-NPD gas chromatography with nitrogen selective detection - GC-FPD gas chromatography with sulphur selective detection     

Blood flow and metabolism in heterotopic cerebellar grafts during hypoglycemia

Summary Hypoglycemia-induced disturbances of brain metabolism and neuronal injury exhibit a distinct predilection for forebrain structures, in particular the caudate-putamen, hippocampus and cerebral cortex, whereas the cerebellum is remarkably resistant. In an attempt to assess the biological basis of this differential regional vulnerability, we have used a neural transplantation technique to compare hemodynamic and metabolic changes in cerebellum during servere hypoglycemia with those in heterotopic cerebellar grafts. To this end, the cerebellar anlage of fetal rat brain (day 15 of gestation) was stereotactically transplanted into the vulnerable caudate-putamen. Following a differentiation period of 8 weeks the grafts had developed into an organotypic population of mature cells with laminar histoarchitecture. Host animals were then subjected to insulin-induced hypoglycemia. After 15 min of isoelectric EEG, blood flow was increased throughout the brain but residual glucose consumption was significantly higher in cerebellum (0.29 mol/g per min) and cerebellar grafts (0.22 mol/g per min) as a result of increased glucose extraction. Hypoglycemia caused a depletion of ATP in all brain structures except cerebellum where normal levels were maintained. Correlation of local ATP content and glucose utilization revealed a threshold-like decline of ATP at a glucose utilization rate of 0.27 mol/g per min. ATP, in consequence, was normal in cerebellum but partially depleted in cerebellar grafts. It is concluded that the resistance of cerebellum to hypoglycemia is due to its capacity for higher glucose extraction at low blood glucose levels, and that this unique intrinsic property is preserved after heterotopic transplantation.Supported in part by the Deutsche Forschungsgemeinschaft (SFB 70)     

Tolerance to ethanol-induced impairment of water escape in rats bred for ethanol sensitivity

Rats selectively bred for ethanol (EtOH)-induced reductions in locomotor activity (least affected = LA; most affected = MA) showed a reversed order of sensitivity (i.e., LA more sensitive) to EtOH-induced (1.75 g/kg, IP) impairment of swimming. Thirty days of daily EtOH intubation began the next day, starting at 3.5 g/kg for 4 days, and increasing by 0.5 g/kg after 4 days at each dose, until 6.0 and 6.5 g/kg were given for 5 days each. Subjects were retested on the swim task (1.75 g/kg, IP) following 10, 20, and 30 days of chronic EtOH, and at 10, 20, and 30 days after cessation of EtOH treatment. Rats of each line and sex showed progressively decreasing peak impairment during the chronic treatment period; impairment increased toward initial levels during the post-treatment period. LA rats were more impaired than MA rats prior to, throughout, and subsequent to the chronic treatment period; a significant positive correlation between initial impairment and impairment after 30 days of chronic EtOH was found. No line differences in rates of tolerance acquisition or loss, or in final levels of tolerance as indicated by post-treatment impairment relative to initial impairment were observed. The similarity of the dynamics of EtOH tolerance in rats selectively bred for sensitivity to its acute effects suggests independent genetic influences upon initial ethanol sensitivity as opposed to acquired ethanol tolerance.     

Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a debilitating autoimmune disease that has traditionally been treated with disease-modifying anti-rheumatic drugs (DMARDs). In the European Union (EU), patients who fail to respond to traditional DMARDs may receive tumor necrosis factor-α (TNF-α) antagonists. However, approximately one-third of patients fail TNF-α antagonists due to adverse effects or lack of efficacy, and there are limited treatment options available to these patients. As knowledge of the underlying immunopathology of RA evolves, new strategies for inhibiting the inflammatory process have emerged. It is well known that activated T cells play a key role in orchestrating the immunopathological mechanisms of RA. Inhibiting the full activation of T cells is a rational strategy in the treatment of RA and represents a novel method of inhibiting disease activity, distinct from inflammatory cytokine blockade. Here, the safety and efficacy of abatacept, a selective T-cell co-stimulation modulator recently approved in the EU, is reviewed in patients with RA who have shown an inadequate response to TNF-α antagonists. In a randomized, placebo-controlled, double-blind, phase III trial of patients with an inadequate response to TNF-α antagonism, abatacept was effective in improving the signs and symptoms of RA, as well as patient-centered outcomes, such as fatigue, disability, and other mental and physical aspects of health-related quality of life. These improvements were sustained through 2 years during the open-label, long-term extension period. In this trial, abatacept demonstrated a safety and tolerability profile similar to placebo. Taken together, these data suggest that selective co-stimulation modulation with abatacept may be a viable option for patients who are refractory to both traditional therapies and TNF-α antagonists. An erratum to this article can be found at     

选择性激光小梁成形术与抗青光眼药物治疗青光眼和高眼压症疗效的Meta分析

背景 选择性激光小梁成形术(SLT)和抗青光眼药物均可用于青光眼或高眼压症(OHT)的治疗,但目前还缺乏比较两种治疗方法的疗效和安全性的循证医学证据. 目的 评价和比较SLT与抗青光眼药物治疗青光眼及OHT的疗效和安全性. 方法 利用计算机检索Pubmed、Embase、Cochrane Controlled Trials Register database、万方数据库2016年5月前发表的关于比较SLT与抗青光眼药物治疗青光眼及OHT疗效的随机对照研究的文献,采用Revman 5.3软件进行Meta分析,疗效评价指标包括眼压下降幅度值(IOPR)和治疗成功率,安全性评价指标包括治疗的不良反应.采用加权均数差值(WMD)分析IOPR,采用比值比(OR)分析随访期间的治疗成功率.结果 纳入6项随机临床对照试验,样本量共361例598眼(高加索人243眼,亚裔291眼,其他人种64眼),研究对象均为青光眼或OHT患者,其中5项研究(431眼)比较了SLT与抗青光眼药物治疗后的IOPR,药物组患者IOPR比SLT组多0.21 mmHg(1 mmHg=0.133 kPa),差异有统计学意义[WMD=-0.21 mmHg;95％置信区间(CI):-0.30,-0.11;P＜0.000 1],各研究间无异质性(I2=0％).纳入的6项研究均比较了2种治疗方法的成功率,药物组成功率高于SLT组,差异有统计学意义(OR=0.57;95％ CI:0.37 ～0.87;P=0.01),各研究间无异质性(I2=13％). 结论 抗青光眼药物和SLT疗法对青光眼和OHT患者均有降眼压作用,但抗青光眼药物的降眼压效果优于SLT.     

Shoulder disability after different selective neck dissections (levels II-IV versus levels II-V): a comparative study

OBJECTIVES/HYPOTHESIS: The objective was to compare the results of clinical and electrophysiological investigations of shoulder function in patients affected by head and neck carcinoma treated with concomitant surgery on the primary and the neck with different selective neck dissections. STUDY DESIGN: Retrospective study of 40 patients managed at the Department of Otolaryngology, University of Brescia (Brescia, Italy) between January 1999 and December 2001. METHODS: Two groups of 20 patients each matched for gender and age were selected according to the type of neck dissection received: patients in group A had selective neck dissection involving clearance of levels II-IV, and patients in group B had clearance of levels II-V. The inclusion criteria were as follows: no preoperative signs of myopathy or neuropathy, no postoperative radiotherapy, and absence of locoregional recurrence. At least 1 year after surgery, patients underwent evaluation of shoulder function by means of a questionnaire, clinical inspection, strength and motion tests, electromyography of the upper trapezius and sternocleidomastoid muscles, and electroneurography of the spinal accessory nerve. Statistical comparisons of the clinical data were obtained using the contingency tables with Fisher's Exact test. Electrophysiological data were analyzed by means of Fisher's Exact test, and electromyography results by Kruskal-Wallis test. RESULTS: A slight strength impairment of the upper limb, slight motor deficit of the shoulder, and shoulder pain were observed in 0%, 5%, and 15% of patients in group A and in 20%, 15%, and 15% of patients in group B, respectively. On inspection, in group B, shoulder droop, shoulder protraction, and scapular flaring were present in 30%, 15%, and 5% of patients, respectively. One patient (5%) in group A showed shoulder droop as the only significant finding. In group B, muscle strength and arm movement impairment were found in 25% of patients, 25% showed limited shoulder flexion, and 50% had abnormalities of shoulder abduction with contralateral head rotation. In contrast, only one patient (5%) in group A presented slight arm abduction impairment. Electromyographic abnormalities were less frequently found in group A than in group B (40% vs. 85% [P = .003]), and the distribution of abnormalities recorded in the upper trapezius muscle and sternocleidomastoid muscle was quite different: 20% and 40% in group A versus 85% and 45% in group B, respectively. Only one case of total upper trapezius muscle denervation was observed in group B. In both groups, electroneurographic data from the side of the neck treated showed a statistically significant increase in latency (P = .001) and decrease in amplitude (P = .008) compared with the contralateral side. There was no significant difference in electroneurographic data from the side with and the side without dissection in either group. Even though a high number of abnormalities was found on electrophysiological testing, only a limited number of patients, mostly in group B, displayed shoulder function disability affecting daily activities. CONCLUSION: The study data confirm that clearance of the posterior triangle of the neck increases shoulder morbidity. However, subclinical nerve impairment can be observed even after selective neck dissection (levels II-IV) if the submuscular recess is routinely dissected.     

A study of experimental cyanide encephalopathy in the acute phase —Physiological and neuropathological correlation

Summary A study was performed to elucidate the significance of various physiological factors contributing to the pathogenesis of experimental cyanide encephalopathy, such as the systemic arterial blood pressure, venous pressure, common carotid blood flow and local blood flow of the cerebral grey and white matters, and blood gas including pH. The histology and topography of the brain damage was also analysed. Twenty-one cats were divided into four groups. The animals in groups 1, 2 and 3 were subjected to continuous infusion of 0.2% sodium cyanide solution and to the ensuing hypotension below 100 mm Hg by administering a ganglion-blocking drug and by respiratory arrest. Severe damage developed in the deep cerebral white matter, corpus callosum, pallidum and substantia nigra, but the damage of the cerebral cortex and hippocampus was not remarkable. The animals in group 4 that were subjected to cyanide infusion without significant hypotension (above 100 mm Hg), but to the same degree of acidosis as that of the the other groups, had similar morphological changes, but to a lesser degree. On the basis of our physiological and morphological findings, we speculated that the pathophysiological factors of tissue hypoxia and subsequent hypotension operated in cyanide leucoencephalopathy. The topographic selectivity seemed to be related to the characteristic cerebral vascular system, and the severity of the white matter lesions was related to the intensity of both hypoxia and hypotension during cyanide infusion, but not to the extent of acidosis, total dose of cyanide or duration of its infusion per se.Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (No. 58770280)