GABAergic modulation of inferior colliculus excitability: role in the ethanol withdrawal audiogenic seizures

The role of the inferior colliculus and GABAeric transmission within this structure in the development of susceptibility to sound-induced seizures in ethanol-dependent rats was examined. Ethanol-dependent rats with bilateral electrolytic lesions which destroyed approximately 50.0 +/- 6.4% of the inferior colliculus failed to exhibit susceptibility to sound-induced seizures. However, comparable medial geniculate body lesions (82.7 +/- 2.7% complete) did not alter wild running, slightly reduced tonus and actually increased clonus susceptibility in rats treated similarly with ethanol. As reported previously, bilateral injection of either muscimol (43-263 pmol/site) or racemic baclofen (520-1580 pmol/site) into the inferior colliculus also suppressed seizure susceptibility. Other studies in ethanol-naive animals found that bilateral microinfusion of (+)-bicuculline methiodide (2 or 20 pmol/min for up to 5 min) into the inferior colliculus induced wild running and clonus closely resembling sound-induced seizure responses in ethanol-dependent rats. Although similar microinjections of (+)-bicuculline methiodide (0.4 pmol/min for 5 min) into the inferior colliculus did not induce seizure activity directly, an increased susceptibility to sound-induced seizures was observed. Electrolytic lesions of the medial geniculate body did not block wild running responses induced by (+)-bicuculline methiodide, but slightly reduced clonus. Five-minute infusions of picrotoxin (200 pmol/min), Ro5-3663 (2000 pmol/min), kainic acid (20 or 200 pmol/min), strychnine (2000 pmol/min) or carbachol 2000 pmol/min) into the inferior colliculus of ethanol-naive rats all induced bicuculline-like seizures. Seizures induced by bicuculline methiodide, picrotoxin or Ro5-3663 occurred within 5 min after the start of infusions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactive role for neurosteroids in ethanol enhancement of gamma-aminobutyric acid-gated currents from dissociated substantia nigra reticulata neurons

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.     

Individual differences in cognition, affect, and performance: behavioral, neuroimaging, and molecular genetic approaches

We describe the use of behavioral, neuroimaging, and genetic methods to examine individual differences in cognition and affect, guided by three criteria: (1) relevance to human performance in work and everyday settings; (2) interactions between working memory, decision-making, and affective processing; and (3) examination of individual differences. The results of behavioral, functional MRI (fMRI), event-related potential (ERP), and molecular genetic studies show that analyses at the group level often mask important findings associated with sub-groups of individuals. Dopaminergic/noradrenergic genes influencing prefrontal cortex activity contribute to inter-individual variation in working memory and decision behavior, including performance in complex simulations of military decision-making. The interactive influences of individual differences in anxiety, sensation seeking, and boredom susceptibility on evaluative decision-making can be systematically described using ERP and fMRI methods. We conclude that a multi-modal neuroergonomic approach to examining brain function (using both neuroimaging and molecular genetics) can be usefully applied to understanding individual differences in cognition and affect and has implications for human performance at work.     

Effects of ethanol on platelet thromboxane formation after ethanol withdrawal in chronic alcoholics: An in vitro study

The effect of ethanol on the formation of platelet thromboxane B2 (TXB2), a stable metabolite of thromboxane A2 (TXA2) was studied in vitro in six chronic alcoholics, admitted for detoxification, and in six healthy volunteers. Immediately after cessation of heavy drinking platelet count and ADP-induced TXB2 formation were lower in alcoholics than in nonalcoholic volunteers (P less than 0.05). Ten days after withdrawal of ethanol platelet count increased, and skin bleeding time shortened (P less than 0.05). Ethanol had no effect on arachidonate-induced platelet TXB2 formation, whereas ethanol added to platelet suspension prior to stimulation by ADP resulted in a concentration-related inhibitory tendency in both alcoholics and nonalcoholic control subjects. This effect of ethanol may be of significance for primary hemostasis in alcoholics.     

Effects of venlafaxine on ethanol withdrawal syndrome in rats

The present study was designed to investigate the effects of venlafaxine, a serotonin and noradrenaline reuptake inhibitor (SNRI), on ethanol withdrawal syndrome in rats. Adult male Wistar rats (187-319 g) were used for the study. Ethanol (7.2%, v/v) was given to rats by a liquid diet for 21 days. Control rats were pair-fed an isocaloric liquid diet containing sucrose as a caloric substitute to ethanol. Venlafaxine (5, 10, 20 and 40 mg/kg) and saline were injected to rats intraperitoneally just before ethanol withdrawal. After the 2nd, 4th and 6th hour of ethanol withdrawal, rats were observed for 5 min, and withdrawal signs that included locomotor hyperactivity, agitation, stereotyped behaviour and wet dog shakes were recorded or rated. A second series of injections was given at the 6th hour after the first one, and rats were then tested for audiogenic seizures. Venlafaxine produced some inhibitory effects on locomotor hyperactivity, stereotypic behaviours and wet dog shakes. However, a two-way anova of the data did not indicate any significant effect. It reduced the incidence of the audiogenic seizures at the 6th hour of ethanol withdrawal. Venlafaxine (20 mg/kg) also prolonged the latency of the seizures significantly. Our results suggest that acute venlafaxine treatment has limited beneficial effects on ethanol withdrawal syndrome in rats.     

The role of carbamazepine and oxcarbazepine in alcohol withdrawal syndrome

Objective: The goal of this review is to evaluate the efficacy and safety of carbamazepine and oxcarbazepine in treatment of alcohol withdrawal syndrome (AWS) and determine the role in therapy of both agents. Methods: Relevant literature was identified through a search of MEDLINE (1966–June 2008), PubMed (1966–June 2008); Cochrane database was performed to identify English‐language publications. Search terms included carbamazepine, oxcarbazepine, AWS, alcoholism, substance syndrome withdrawal. Results: In seven studies, including 612 patients, carbamazepine demonstrated significant reduction in alcohol withdrawal scores. However, in comparative trials with a benzodiazepine agent, carbamazepine’s ability to prevent alcohol withdrawal seizures (OR = 0·93; 95% CI = 0·06–14·97, P = NS) and delirium tremens (DTs; OR = 1·25; 95% CI = 0·28–5·64, P = NS) was uncertain as a result of insufficient patient enrolment. In three trials, carbamazepine failed to reduce alcohol withdrawal symptoms possibly as a result of delayed administration, inadequate dosage or inadequate sample size. At daily doses of 800 mg either fixed or tapered over 5–9 days, carbamazepine was well tolerated, and safely administered when blood alcohol concentration dropped below 0·15%. The role of oxcarbazepine in AWS is undefined because of inconsistent findings in two trials. Conclusion: Carbamazepine has demonstrated safety, tolerability and efficacy in treatment of moderate to severe symptoms of alcohol withdrawal in the inpatient setting. However, trials of carbamazepine provide inconclusive evidence for prevention of alcohol withdrawal seizures and DTs in comparison with benzodiazepines. Benzodiazepines remain the primary treatment of moderate to severe AWS.     

Differential change in neuroactive steroid sensitivity during ethanol withdrawal

The progesterone metabolite 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-P or allopregnanolone) is a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. Although it is well documented that chronic ethanol (EtOH) administration produces cross-tolerance to the positive modulatory effect of benzodiazepines and GABA at GABA(A) receptors, recent findings suggest that sensitivity to 3alpha,5alpha-P is enhanced during EtOH withdrawal. In addition, EtOH-naive inbred strains of mice, which differ in EtOH withdrawal severity (DBA/2 > C57BL/6), had marked differences in behavioral sensitivity to 3alpha,5alpha-P. Therefore, the present study was conducted to determine whether C57BL/6 (B6) and DBA/2 (D2) mice would be differentially sensitive to several of the pharmacological effects of 3alpha,5alpha-P during EtOH withdrawal. Male mice were exposed to EtOH vapor or air for 72 h. During withdrawal from EtOH, animals were injected with 3alpha,5alpha-P (0, 3.2, 10, or 17 mg/kg i.p.) and tested for activity and anxiolysis on the elevated plus maze, muscle relaxation, ataxia, and seizure protection following pentylenetetrazol. Sensitivity to the anticonvulsant effect of 3alpha,5alpha-P was enhanced during EtOH withdrawal in B6, but not D2 mice. In contrast, sensitivity to the muscle relaxant effects of 3alpha,5alpha-P was reduced in EtOH-withdrawing B6 and D2 mice, with a suggestion of decreased sensitivity to the anxiolytic effect of 3alpha,5alpha-P during EtOH withdrawal in B6. These results suggest that sensitization to the anticonvulsant effect of 3alpha,5alpha-P during EtOH withdrawal does not generalize across all genotypes nor does it generalize to all of the pharmacological effects of 3alpha,5alpha-P.     

Neurochemical aspects of ethanol dependence and withdrawal reactions in mice

Mice were made physically dependent on ethanol by a 3-day period of alcohol inhalation with small daily injections of pyrazole. During this treatment the concentrations of norepinephrine, dopamine and 5-hydroxytryptamine were increased in brain with concomitant decrease in gamma-aminobutyric acid, RNA and DNA. However, the monoamine concentrations showed complete regression to normal levels at the time of maximal withdrawal seizure when GABA level was still elevated above the control values. Brain RNA and DNA concentrations remained low at this period. During the recovery phase, the pattern of neuronal components was almost the same as was observed at maximal withdrawal seizures. Pyrazole by itself did not produce significant changes in concentrations of the neuronal components of brain.     

Ethanol withdrawal in mice bred to be genetically prone or resistant to ethanol withdrawal seizures

We are engaged in a selective breeding program developing lines of mice which differ in severity of withdrawal convulsions after ethanol treatment. Withdrawal seizure prone (WSP) mice show greater handling-induced convulsion scores than withdrawal seizure resistant (WSR) mice after 3 days of ethanol intoxication. In the present experiments, we sought to characterize these mice further as a model of genetic susceptibility to ethanol dependence and withdrawal. During withdrawal after chronic treatment with ethanol, WSP mice displayed more severe handling-induced convulsions and tremor than WSR mice, and tended to show greater reduction of exploratory activity. WSP and WSR mice did not differ in ethanol metabolism after acute treatment with ethanol alone or after chronic treatment with ethanol and pyrazole, an alcohol dehydrogenase inhibitor. Six to 10 hr after an acute injection of ethanol, WSP and WSR mice showed elevated handling-induced convulsions. This elevation was more pronounced in WSP mice than in WSR mice. WSP mice also showed slightly more severe convulsions than WSR mice when treated with saline or pyrazole alone. In summary, WSP and WSR mice treated with identical doses of ethanol differ in several symptoms of withdrawal, whereas not differing in ethanol metabolism. These mice constitute a useful population in which to study the molecular mechanisms of ethanol dependence and withdrawal.     

The behavioral role of physical therapy in pain management

Physical therapy assessment and treatment of chronic pain patients focuses on increasing functional ability and decreasing disability. A range of behavioral techniques discussed in this paper are used to achieve these goals.     

Alcohol dependence and withdrawal: a genetic animal model

Using the techniques of selective breeding, mouse lines have been developed that express severe (Withdrawal Seizure Prone: WSP) or mild (Withdrawal Seizure Resistant: WSR) handling induced convulsions after cessation of chronic ethanol exposure. These lines differ at least ten-fold in severity of withdrawal after identical ethanol treatment. One feature of the genetic model is that other traits which distinguish these lines are presumably influenced by those genes determining ethanol withdrawal severity. WSP and WSR mice do not differ markedly in the metabolism of ethanol. In addition to handling induced convulsions, they also differ in other withdrawal signs: for example, WSP mice show more pronounced tremor. WSP and WSR mice do not differ in sensitivity to ethanol's hypothermic, anesthetic, or locomotor stimulant effects, nor in the magnitude of tolerance development to these responses. This suggests that sensitivity, tolerance and dependence are distinct genetic entities. WSP mice also display more severe withdrawal from diazepam, phenobarbital, and nitrous oxide than WSR mice, suggesting that some genes generally predispose mice to withdrawal from depressants. WSP mice display withdrawal handling induced convulsions after a single dose of ethanol, pentobarbital, or diazepam. The effective dose for producing drug seizures is not markedly different between WSP and WSR mice for a number of compounds with varied mechanisms of action. However, WSP mice are more sensitive than WSR mice to the effects of acute doses of convulsants to elevate handling induced convulsions. WSP mice have more binding sites in hippocampus for the N-methyl-D-aspartate antagonist MK 801. Binding of this ligand is increased during ethanol dependence in both mouse lines.(ABSTRACT TRUNCATED AT 250 WORDS)     

The broken genome: genetic and pharmacologic approaches to breaking DNA

The RecQ family of DNA helicases consists of specialized DNA unwinding enzymes that promote genomic stability through their participation in a number of cellular processes, including DNA replication, recombination, DNA damage signaling, and DNA repair pathways. Mutations resulting in the inactivation of some but not all members of the RecQ helicase family can lead to human syndromes which are characterized by marked chromosomal instability and an increased predisposition to cancer. An evolutionarily conserved interaction between RecQ helicases and topoisomerase 3s has been established, and this interaction is important in the regulation of recombination and genomic stability. Topoisomerases are critical in the cell because they relieve helical stress that arises when DNA is unwound. Topoisomerases function by breaking and rejoining DNA. By inhibition of the rejoining function, topoisomerase inhibitors are potent chemotherapeutic agents that have been used successfully in the treatment of hematologic malignancies and other cancers. This review discusses the roles of RecQ helicases in genomic stability, the interplay between RecQ helicases and topoisomerase 3s, and current and future prospects for targeting these interactions to develop novel anticancer therapies.     

The role of genetic diversity in cancer

The role of genetic heterogeneity within neoplasms is increasingly recognized as important for understanding the dynamics of cancer progression, cancer stem cells, and therapeutic resistance, and there is interest in intratumoral heterogeneity measurements as potential biomarkers for risk stratification. In this issue of the JCI, Park et al. characterize this genetic diversity in carcinoma in situ and in invasive regions from 3 types of human breast cancers and lay the groundwork for translation of these measures to the clinic. Although there are clear suggestions that diversity may be important in the establishment and progression of cancers (1), it is unclear how diversity should be defined. Should we use genetic or phenotypic markers? How can we account for epigenetic diversity? Should we look at large samples or small ones, and how many biopsies should we sample in order to accurately estimate the underlying diversity of the neoplasm? The problems of defining diversity and characterizing the number of cancer clones are not new and have parallels to problems encountered in other fields. Ecologists have created various measures to estimate the number and abundance of species (2); even in literature, calculating the number of words Shakespeare knew from his existing corpus (3) is analogous to determining the number of cancer clones in a tumor from a small number of samples. Heterogeneity in neoplasms has long been recognized (4–7), but has only recently been systematically investigated, and much can be gained by applying these methodologies to cancer and precancerous lesions (8–10). As Park et al. clearly demonstrate in their study in this issue of the JCI (11), this is not merely an academic exercise, as the level of heterogeneity in a neoplasm may have important clinical implications as a biomarker of risk stratification.     

Efficacy and effectiveness approaches in behavioral treatment trials

The objective is to clarify the distinction between efficacy and effectiveness approaches and to discuss how these approaches can be used in a complementary way in the development, evaluation, and implementation of behavioral treatments for primary headache in various settings. Efficacy studies, with an emphasis on internal validity, are experiments that evaluate treatment response in an ideal, highly controlled research environment. Despite their methodological strengths, efficacy studies are limited in their ability to estimate the treatment effects that can be expected in clinical practice settings. Effectiveness studies, with an emphasis on external validity, are outcome studies with less controls that evaluate treatment response in settings more representative of clinical practice. Effectiveness studies, however, are limited in their ability to determine the causal link between treatment and response. Based on the four-phase model used in new drug development, a three-phase linear progression model is presented for behavioral treatment studies. This model provides for pilot testing, efficacy testing, and effectiveness testing of behavioral treatments so that there is appropriate evaluation from initial promise of a developing treatment to implementation and dissemination to various treatment delivery settings.     

Interaction of the nicotinic cholinergic system with ethanol withdrawal

The observation that alcohol and nicotine are commonly abused together suggests that the two drugs have common sites of action. In vitro studies indicate that nicotinic acetylcholine receptor (nAChR) function is enhanced by ethanol. Furthermore, some ethanol-related behaviors are associated with a region of mouse chromosome 2 that contains the gene encoding the alpha4 subunit of the nAChR (Chrna4). We have identified a polymorphism in Chrna4 that results in an alanine (A) or threonine (T) residue at position 529 in the second intracellular loop of the protein. Nicotinic receptors expressing the A variant have greater responses to nicotine and ethanol than receptors with the T variant when measured in vitro, but the possible effects of the polymorphism on the severity of ethanol withdrawal have not been assessed. The handling-induced convulsion (HIC) assay is an established method for studying drug withdrawal in vivo. We monitored the HIC responses of mice for 8 h after an injection of ethanol (4 g/kg). A survey of 16 mouse strains, as well as previously published data, indicated an association of the A/T polymorphism with ethanol withdrawal. This association was also found in wild-type animals from an F2 intercross of the A/J (A529-genotype) strain with C57BL/6J (T529-genotype) mice that also lack expression of the beta2 nAChR subunit. Beta2 -/- animals, which do not express alpha4beta2 nAChRs in the brain, exhibited significantly lower HIC responses and no effect of the polymorphism. These results suggest that the nicotinic cholinergic system and the A/T polymorphism modulate ethanol withdrawal.     

The ego activation method: Anin vivo cognitive therapy integrating behavioral and psychodynamic approaches

This article discusses an innovative psychotherapeutic approach, known as the ego activation method, which expedites progress in the treatment of anxiety states and nonbipolar, nonpsychotic, acutely depressed outpatients. The method, readily integrated into approaches of diverse orientations, systematically provides patients with experiences with real problems and risks in the context of the therapy sessions. The sessions consist not simply of a series of “verbal exchanges” but of “verbal exchanges plus actions” with a wide array of specially devised therapeutic tasks — over 200 have been developed. The tasks establish a working alliance between the patient and the therapist, activate ego adaptive processes, and assist the patient in developing mastery and control over his/her problems. The method implements therapeutic success through addressing three active ingredients in the therapeutic process: (1) assisting the patient to assume a more active, assertive role; (2) promoting internal locus of control and self-responsibility; and (3) enhancing the patient's sense of mastery. References to detailed case reports are provided.     

肥胖康复中的行为干涉治疗

行为干涉包括调整那些与肥胖的维持和发展有关的行为的系统应用.大多数行为干涉指自我监测、刺激控制、应激处理、社会支持、事故处理、处理问题、体育锻炼、防止反弹、认识重塑等.这些干涉在肥胖者短期体重减轻疗效较好,但对长期保持较低的体重效果略差.因为肥胖是个不易治愈的慢性状态,所以行为干涉需要覆盖面广,包括生存质量,良好的心理素质,较低的心血管危险因素,持续的治疗模式而非短暂的、限时的收效.     

Cognitive and behavioral approaches in the treatment of obesity

The research reviewed within this article provides support for both the cognitive and behavioral components of cognitive behavioral weight-loss interventions. Lifestyle based treatments have produced markedly improved results in the past 20 years, in part attributable to changes in treatment structure. Use of pretreatment participant preparation strategies, extended treatment periods with clearly defined weight-loss goals, combining multiple dietary and physical activity strategies, and increasing emphasis on long-term provider contact and relapse prevention have modestly improved long-term weight maintenance. Several investigators have emphasized the need to incorporate additional cognitive components into the cognitive-behavioral treatment of obesity to improve both short- and long-term outcomes. Furthermore, continued insights into metabolic changes producing an energy gap after weight loss should no doubt continue to refine insights into the behavioral requirements of long-term weight loss. Despite increased awareness and behavioral treatment advances, the worldwide prevalence of obesity and weight-related chronic illnesses continues to expound. Behavioral treatment is inherently challenging and time-consuming, and readily available to only a fraction of the population who may benefit from inclusion. Several investigators have cautioned that individual or small group-based interventions are insufficient to serve the population masses requiring treatment, and that continued development of community or Web-based programs, and community-development tactics to increase healthy lifestyles, are needed. The call has been sounded to conceptualize obesity as a chronic health condition requiring lifelong treatment. As such, the conceptualization of cognitive-behavioral therapies as a one-time treatment is passe′ . As the current number of obesity specialists and behaviorally trained professionals is insufficient to combat this problem; an increased emphasis upon training nontraditional weight specialists and nonbehavioral community providers is obviated.     

Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal.

This study examined in baboons various behavioral effects of zolpidem, a short-acting imidazopyridine hypnotic which has selectivity for subtypes of the benzodiazepine receptor. Intravenous drug self-injection was studied under a fixed-ratio 80- or 160-response schedule with a 3-hr timeout after each injection. Maximal rates of self-injection maintained by zolpidem (0.01-1 mg/kg) were consistently higher than those maintained by vehicle and the benzodiazepine hypnotic triazolam. Substitution of vehicle after about 2 weeks of zolpidem self-injection (7-8 mg/kg/day) resulted in a time-limited suppression of food pellet intake, indicating a drug withdrawal effect. In a drug discrimination study, baboons were trained to discriminate either lorazepam (1.8 mg/kg p.o.) or pentobarbital (10 mg/kg p.o.) from the no-drug condition. Zolpidem (0.1-18 mg/kg p.o.) occasioned both lorazepam- and pentobarbital-appropriate responding (greater than 80%) in a dose-dependent manner. In a final experiment, zolpidem (3.2 or 5.6 mg/kg i.m.) produced ataxia and sedation that progressively decreased over 7 consecutive days of administration. The withdrawal, discriminative stimulus effects and tolerance shown with zolpidem were similar to those shown previously with benzodiazepines under similar conditions. The rates of self-injection of zolpidem were similar to those maintained by intermediate duration barbiturates (e.g., pentobarbital) and higher than those maintained by 11 benzodiazepines studied previously under similar conditions. Further research on the reinforcing effects of zolpidem may provide useful insights into mechanisms underlying the maintenance of behavior by compounds acting through the benzodiazepine receptor.