[Benzodiazepines should still be first-line treatment for alcohol withdrawal].

In this review, we summarize the evidence for benzodiazepines and barbiturates as alcohol withdrawal treatment and outline a treatment guideline. A number of randomized controlled trials (RCTs) indicate that benzodiazepine treatment decreases alcohol withdrawal seizures and is safe. For barbiturates, only a few RCTs have been undertaken, and barbiturates were not found to be superior to benzodiazepines. Consequently, we suggest that benzodiazepines should still be first-line treatment for alcohol withdrawal.

Anti-anxiety self-medication in rats: oral consumption of chlordiazepoxide and ethanol after reward devaluation.

Rats increased preference for ethanol after sessions of appetitive extinction, but not after acquisition (reinforced) sessions (Manzo et al., 2014). Drinking was not influenced by appetitive extinction in control groups with postsession access to water, rather than ethanol. Because ethanol has anxiolytic properties in tasks involving reward loss, these results were interpreted as anti-anxiety self-medication. The present experiment tested the potential for self-medication with the prescription anxiolytic chlordiazepoxide, a benzodiazepine with an addictive profile used in the treatment of anxiety disorders. To test this hypothesis, Wistar rats exposed to a 32-to-4% sucrose devaluation received a two-bottle, 2-h preference test immediately after consummatory training. One bottle contained 1 mg/kg of chlordiazepoxide, 2% ethanol, or water for different groups (the second bottle contained water for all groups). Three additional groups received the same postsession preference tests, but were exposed to 4% sucrose during consummatory training. Rats showed suppression of consummatory behavior after reward devaluation relative to unshifted controls. This effect was accompanied by a selective increase in preference for chlordiazepoxide and ethanol. Downshifted animals with access to water or unshifted controls with access to the anxiolytics failed to exhibit postsession changes in preference. Similar results were observed in terms of absolute consumption and consumption relative to body weight. This study shows for the first time that a prescription anxiolytic supports enhanced voluntary consumption during periods of emotional distress triggered by reward loss. Such anti-anxiety self-medication provides insights into the early stages of addictive behavior.

Cost-effectiveness analysis of baclofen and chlordiazepoxide in uncomplicated alcohol-withdrawal syndrome.

OBJECTIVES: Benzodiazepines (BZDs) are the first-line drugs in alcohol-withdrawal syndrome (AWS). Baclofen, a gamma-aminobutyric acidB (GABAB) agonist, controls withdrawal symptoms without causing significant adverse effects. The objective of this study was to compare the cost-effectiveness of baclofen and chlordiazepoxide in the management of uncomplicated AWS. MATERIALS AND METHODS: This was a randomized, open label, standard controlled, parallel group study of cost-effectiveness analysis (CEA) of baclofen and chlordiazepoxide in 60 participants with uncomplicated AWS. Clinical efficacy was measured by the Clinical Institute Withdrawal Assessment for alcohol (CIWA-Ar) scores. Lorazepam was used as supplement medication if withdrawal symptoms could not be controlled effectively by the study drugs alone. Both direct and indirect medical costs were considered and the CEA was analyzed in both patient's perspective and third-party perspective. RESULTS: The average cost-effectiveness ratio (ACER) in patient's perspective of baclofen and chlordiazepoxide was Rs. 5,308.61 and Rs. 2,951.95 per symptom-free day, respectively. The ACER in third-party perspective of baclofen and chlordiazepoxide was Rs. 895.01 and Rs. 476.29 per symptom-free day, respectively. Participants on chlordiazepoxide had more number of symptom-free days when compared with the baclofen group on analysis by Mann-Whitney test (U = 253.50, P = 0.03). CONCLUSION: Both study drugs provided relief of withdrawal symptoms. Chlordiazepoxide was more cost-effective than baclofen. Baclofen was relatively less effective and more expensive than chlordiazepoxide.

Drug effects on multiple and concurrent schedules of ethanol- and food-maintained behaviour: context-dependent selectivity.

BACKGROUND AND PURPOSE: Drugs that more potently or effectively reduce ethanol-maintained behaviour versus an alternative are considered selective and are considered promising pharmacotherapies for alcoholism. Such results are often obtained using separate groups or multiple schedules where ethanol and the alternative are available alone or sequentially. Recently, we observed that when ethanol and food were available sequentially under a multiple schedule, fluvoxamine and varenicline were selective; yet this selectivity disappeared when ethanol and food were concurrently available. EXPERIMENTAL APPROACH: We examined the generality of these findings by comparing doses of several drugs required to decrease ethanol- and food-maintained responding under a multiple schedule and under a concurrent schedule. Effects were determined for chlordiazepoxide, 2,5-dimethoxy-4-iodoamphetamine (DOI), meta-chlorophenylpiperazine (mCPP), morphine, naltrexone and d-amphetamine. KEY RESULTS: Under the multiple schedule, ED50 values for decreases in ethanol-maintained responding were significantly different and lower than ED50 s for decreases in food-maintained responding (demonstrating selectivity) for each drug except for chlordiazepoxide (which was equipotent) and naltrexone (which did not affect responding). However, this selectivity vanished or even inverted under the concurrent schedule, such that ED50 values for decreasing ethanol- and food-maintained responding were not different (or, following DOI, the ED50 for food-maintained responding was lower than for ethanol-maintained responding). CONCLUSIONS AND IMPLICATIONS: Results are consistent with those seen following fluvoxamine and varenicline administration, and suggest that selectivity is assay-dependent. These results indicate the need for careful interpretation of selective drug effects, especially when obtained in situations where ethanol or the alternative is the only programmed reinforcement available.

Assessing anxiety in C57BL/6J mice: a pharmacological characterization of the open-field and light/dark tests.

INTRODUCTION: In order to assess anxiety in mammals various tests and species are currently available. These current assays measure changes in anxiety-like behaviors. The open-field and the light/dark are anxiety tests based on the spontaneous behavior of the animals, with C57BL/6J mice being a frequently used strain in behavioral studies. However, the suitability of this strain as a choice in anxiety studies has been questioned. In this study, we performed two pharmacological characterizations of this strain in both the open-field and the light/dark tests. METHODS: We examined the changes in the anxiety-like behaviors of C57BL/6J mice exposed to chlordiazepoxide (CDP), an anxiolytic drug, at doses of 5 and 10 mg/kg, picrotoxine (PTX), an anxiogenic drug, at doses of 0.5 and 1 mg/kg, and methylphenidate (MPH), a psychomotor stimulant drug, at doses of 5 and 10 mg/kg, in a first experiment. In a second experiment, we tested CDP at 2.5 mg/kg, PTX at 2 mg/kg and MPH at 2.5 mg/kg. RESULTS: Results showed an absence of anxiolytic-like effects of CDP in open-field and light/dark tests. Light/dark test was more sensitive to the anxiogenic effects of PTX than the open-field test. Finally, a clear anxiogenic effect of MPH was observed in the two tests. DISCUSSION: Although C57BL/6J mice could not be a sensitive model to study anxiolytic effects in pharmacological or behavioral interventions, it might be a suitable model to test anxiogenic effects. Further studies are necessary to corroborate these results.

Assessing anxiety in C57BL/6J mice: a pharmacological characterization of the zero maze test.

INTRODUCTION: Anxiety disorders affect the quality of life and good health of millions of people over the world. Because clinical trials are expensive and frequently show high rates of placebo responses, animal models have become an important tool for drug discovery and brain research. Zero maze is a commonly used test to assess anxiety-like levels in mice, being the C57BL/6J strain one of the most widely used. However, only few studies have focused on the pharmacological characterization of this strain in the various anxiety tests. METHODS: In this study, we analyzed the changes in the anxiety-like behaviors of mice exposed to chlordiazepoxide (CLZ), as an anxiolytic drug, at doses of 2.5, 5 and 10mg/kg, picrotoxine (PTX), as an anxiogenic drug, at doses of 0.5, 1 and 2mg/kg, and methylphenidate (MPH), as a psychomotor stimulant, at doses of 2.5, 5 and 10mg/kg. Data were hand recorded in situ by an observer and through a camcorder by computer software. RESULTS: Results showed that CLZ and MPH had an anxiogenic effect at the two highest doses. Only CLZ at 2.5mg/kg reduced the anxiety-like levels of mice. Moreover, PTX exerted an anxiogenic effect in mice only at 2mg/kg. The drugs affecting the anxiety-like levels also affected the activity levels. Thus, the differences might have been mediated by changes in activity levels. DISCUSSION: Globally, these data demonstrate that the results obtained from the zero maze test are difficult to interpret when the C57BL/6J strain is used. On the other hand, high doses of substances that interact with the GABAergic system, as CLZ, can produce sedation in these mice. In contrast, high doses of GABAA antagonists, as PTX, are necessary if anxiogenic effects should be observed. Further investigations with this strain are necessary in order to corroborate the results of the present study.

Role of gamma-aminobutyric acid type A (GABAA) receptor subtypes in acute benzodiazepine physical dependence-like effects: evidence from squirrel monkeys responding under a schedule of food presentation.

RATIONALE: Assays of schedule-controlled responding can be used to characterize the pharmacology of benzodiazepines and other GABAA receptor modulators, and are sensitive to changes in drug effects that are related to physical dependence. OBJECTIVE: The present study used this approach to investigate the role of GABAA receptor subtypes in mediating dependence-like effects following benzodiazepine administration. METHODS: Squirrel monkeys (n = 6) were trained on a fixed-ratio schedule of food reinforcement. Initially, the response rate-decreasing effects of chlordiazepoxide (0.1-10 mg/kg; nonselective GABAA receptor agonist), zolpidem (0.032-1.0 mg/kg; α1 subunit-containing GABAA subtype-preferring agonist), and HZ-166 (0.1-10 mg/kg; functionally selective α2 and α3 subunit-containing GABAA receptor agonist) were assessed. Next, acute dependence-like effects following single injections of chlordiazepoxide, zolpidem, and HZ-166 were assessed with flumazenil (0.1-3.2 mg/kg; nonselective GABAA receptor antagonist). Finally, acute dependence-like effects following zolpidem administration were assessed with ßCCt and 3-PBC (0.1-3.2 mg/kg and 0.32-10 mg/kg, respectively; α1 subunit-containing GABAA receptor antagonists). RESULTS: Chlordiazepoxide, zolpidem, and HZ-166 produced dose- and time-dependent decreases in response rates, whereas flumazenil, ßCCT, and 3-PBC were ineffective. After the drug effects waned, flumazenil produced dose-dependent decreases in response rates following administration of 10 mg/kg chlordiazepoxide and 1.0 mg/kg zolpidem, but not following any dose of HZ-166. Further, both ßCCT and 3-PBC produced dose-dependent decreases in response rates when administered after 1.0 mg/kg zolpidem. CONCLUSIONS: These data raise the possibility that α1 subunit-containing GABAA receptors play a major role in physical dependence-related behaviors following a single injection of a benzodiazepine.

Orexin-1 receptor antagonism fails to reduce anxiety-like behaviour in either plus-maze-naïve or plus-maze-experienced mice.

Although several lines of evidence have recently implicated orexins and their receptors in fear and anxiety, there is also a growing number of apparently inconsistent and/or negative findings. In the present study, we have used ethological methods to comprehensively profile the behavioural effects of the orexin-1 receptor antagonist SB-334867 (3-30 mg/kg) in mice exposed to the elevated plus-maze. Two experiments were performed, the first involving test-naïve animals and the second using prior undrugged experience of the maze to induce a qualitatively different emotional response to that seen on first exposure. In Experiment 1, a reference benzodiazepine (chlordiazepoxide, CDP, 15 mg/kg) produced a robust anxioselective profile comprising substantial increases in open arm exploration and reduced risk assessment without any signiifcant change in general activity levels. In contrast, SB-334867 failed to produce any behavioural effects over the dose range tested. In Experiment 2, 5 min undrugged experience of the maze 24h prior to testing increased open arm avoidance and abolished the anxiolytic efficacy of CDP. Despite this altered baseline, SB-334867 again failed to alter plus-maze behaviour. These findings agree with several recent reports that orexin receptor antagonists, such as SB-334867 and almorexant, do not alter basal anxiety levels in rats but markedly contrast with the anxiolytic-like effects of the same agents when anxiety levels have been exacerbated by fear conditioning, drug challenge or hypercapnia. This unique pattern of activity suggests that orexin receptor antagonists may have therapeutic value in those clinical anxiety disorders characterised by intense emotional arousal.

Working memory in the odor span task: effects of chlordiazepoxide, dizocilpine (MK801), morphine, and scopolamine.

RATIONALE: A number of tasks are used to assess working memory in rodents, but the odor span task (OST) is unique in studying performance as a function of the number of stimuli to remember. OBJECTIVES: The purpose of the present study was to better characterize the behavioral pharmacology of the OST by exploring the effects of several amnestic agents including an NMDA antagonist (dizocilpine), a positive GABA-A modulator (chlordiazepoxide), an anticholinergic compound (scopolamine), and as a negative control, an opiate receptor agonist (morphine). METHODS: Rats were trained to perform on the OST which is a non-match-to-sample procedure with an incrementing number of sample odors to remember as the session progresses. Trials with a simple odor discrimination task (SD) were interspersed to provide a control for effects unrelated to memory load. RESULTS: All four drugs disrupted performances on the OST task in a dose-dependent fashion, but only the NMDA antagonist dizocilpine produced impairments that were clearly dependent on the number of stimuli to remember. Dizocilpine impaired OST performance at a dose (0.1 mg/kg) that did not affect SD, and that impairment depended on memory load. Chlordiazepoxide (3.0 mg/kg) also produced amnestic effects that were manifest by shorter memory spans and runs of correct responding. In contrast, morphine and scopolamine impaired OST accuracy only at doses that also disrupted SD (18.0 and 0.3 mg/kg, respectively). CONCLUSIONS: These results provide evidence of NMDA and benzodiazepine modulation of working memory as assessed by the OST.

Unplanned alcohol withdrawal: a survey of consecutive admissions to an acute medical unit in 2010 and 2011.

BACKGROUND: Alcohol-related presentations to hospital have been increasing in the UK in recent years, including the occurrence of acute withdrawal. This study sought to better characterize the clinical features, patterns of treatment and outcomes in this patient group. METHODS: Patients admitted to the Acute Medical Unit of York Hospital due to acute alcohol withdrawal are normally treated according to a protocol that involves both fixed-dose and symptom-triggered drug administration. Admissions between 2010 and 2011 inclusive were studied. RESULTS: There were 211 admission episodes solely due to acute alcohol withdrawal, involving 127 patients (97 men, 76.4%) with median age of 45 years (interquartile range: 39-52 years). There was a high prevalence of depression (34%), alcoholic liver disease (22%) and drug misuse (12%). Total dose of chlordiazepoxide varied between 0 and 610 mg and tapered rapidly after the first day of admission. Vitamin supplements were administered to >90% of patients, including parenteral and oral in 74%, parenteral alone in 9% and oral alone in 9%. A specialist alcohol nurse reviewed patients while in hospital in 40% of cases. Approximately one-third of patients had multiple admissions for alcohol withdrawal during the study period. CONCLUSION: A high prevalence of physical and mental health disorders was observed. The local policy permitted high initial chlordiazepoxide doses and prompt downward titration, with a broad range of doses between individuals. Approximately 10% required no specific therapy, and there may be opportunities for developing alternative pathways for delivery of care in an ambulatory setting for these patients.

The effect of chlordiazepoxide on measures of activity and anxiety in Swiss-Webster mice in the triple test.

The effects of the anxiolytic drug chlordiazepoxide (CDZ) on general activity and anxiety-related behaviour of male and female Swiss-Webster mice were investigated in the triple test, which combines the open field (OF), elevated-plus maze (EPM) and the light-dark box (LDB). Mice were injected with saline or CDZ (1.0, 7.5 or 15.0 mg/kg) and their behaviour was observed for 15 min in the triple test on each of two days. On day 1, increasing doses of CDZ increased open arm exploration and total distance travelled, and decreased risk assessments in the EPM. In the LDB, CDZ increased time in the light compartment and number of transitions between compartments. In spite of habituation to the apparatus, CDZ increased the number of transitions in the LDB, increased percent time in the open arms and total distance travelled in the EPM on day 2. Thus, there was a significant effect of CDZ in the triple test on both days, even though there was habituation to the apparatus after day 1. These results show that the drug effect was independent of the day effect and that there was no one-trial tolerance effect in the triple test of anxiety.

Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and D-cycloserine.

RATIONALE AND OBJECTIVE: Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, D: -cycloserine (DCS), in C57BL/6 mice were compared. MATERIALS AND METHODS: Following a palatability test (Experiment 1), Experiments 2-6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task. RESULTS: CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 3-7) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre-session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two-lever food-reinforced task (Experiment 7). CONCLUSIONS: The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated.

The amphetamine-chlordiazepoxide mixture, a pharmacological screen for mood stabilizers, does not enhance amphetamine-induced disruption of prepulse inhibition.

In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (-) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16mg/kg) and (-) ephedrine (50mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d-amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120-240mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d-amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited.

Reinforcement magnitude modulation of rate dependent effects in pigeons and rats.

Response rate can influence the behavioral effects of many drugs. Reinforcement magnitude may also influence drug effects. Further, reinforcement magnitude can influence rate-dependent effects. For example, in an earlier report, we showed that rate-dependent effects of two antidepressants depended on reinforcement magnitude. The ability of reinforcement magnitude to interact with rate-dependency has not been well characterized. It is not known whether our previous results are specific to antidepressants or generalize to other drug classes. Here, we further examine rate-magnitude interactions by studying effects of two stimulants (d-amphetamine [0.32-5.6 mg/kg] and cocaine [0.32-10 mg/kg]) and two sedatives (chlordiazepoxide [1.78-32 mg/kg] and pentobarbital [1.0-17.8 mg/kg]) in pigeons responding under a 3-component multiple fixed-interval (FI) 300-s schedule maintained by 2-, 4-, or 8-s of food access. We also examine the effects of d-amphetamine [0.32-3.2 mg/kg] and pentobarbital [1.8-10 mg/kg] in rats responding under a similar multiple FI300-s schedule maintained by 2- or 10- food pellet (45 mg) delivery. In pigeons, cocaine and, to a lesser extent, chlordiazepoxide exerted rate-dependent effects that were diminished by increasing durations of food access. The relationship was less apparent for pentobarbital, and not present for d-amphetamine. In rats, rate-dependent effects of pentobarbital and d-amphetamine were not modulated by reinforcement magnitude. In conclusion, some drugs appear to exert rate-dependent effect which are diminished when reinforcement magnitude is relatively high. Subsequent analysis of the rate-dependency data suggest the effects of reinforcement magnitude may be due to a diminution of drug-induced increases in low-rate behavior that occurs early in the fixed-interval.

Chlordiazepoxide and lavender oil alter unconditioned anxiety-induced c-fos expression in the rat brain.

Lavender oil has a long history of use for treating anxiety, but only recent research has examined its effects using standard behavioural methods used to test novel drugs. The aim of this study was to investigate the effects of inhaled lavender oil on anxiety related behaviour of rats in the open field and to compare them with the effects of chlordiazepoxide (CDP), a typical anxiolytic drug. Additionally c-fos immunochemistry was used to investigate whether lavender oil produced the same pattern of c-fos expression as CDP in eight different brain areas associated with anxiety. As previously found, lavender oil showed anxiolytic properties in the open field similar to but not as extensive as those of CDP. Immunochemistry results indicated that exposure to the open field increased c-fos expression, while CDP reversed the effects of this behavioural stressor on c-fos expression in all brain regions examined except the central nucleus of the amygdala, where c-fos expression increased. Lavender oil had similar effects to CDP on the paraventricular nucleus of the hypothalamus, the dorsomedial hypothalamic nucleus and the central nucleus of the amygdala. These results strengthen the suggestion that inhaling lavender oil has anxiolytic behavioural effects, but they are weaker than the effects of benzodiazepines, and there is limited evidence that they are mediated by the same neural processes.

Alcohol withdrawal syndrome: symptom-triggered versus fixed-schedule treatment in an outpatient setting.

AIMS: To investigate whether, in the treatment with chlordiazepoxide for outpatient alcohol withdrawal, there are advantages of symptom-triggered self-medication over a fixed-schedule regimen. METHODS: A randomized controlled trial in outpatient clinics for people suffering from alcohol dependence (AD) and alcohol-related problems; 165 adult patients in an outpatient setting in a specialized alcohol treatment unit were randomized 1:1 to either a symptom-triggered self-medication or tapered dose, using chlordiazepoxide. Alcohol withdrawal symptoms, amount of medication, duration of symptoms, time to relapse and patient satisfaction were measured. Patients assessed their symptoms using the Short Alcohol Withdrawal Scale (SAWS). Patient satisfaction was monitored by the Diabetes Treatment Satisfaction Questionnaire. We used the Well-Being Index and the European addiction severity index for the 1-year follow-up. RESULTS: We found no differences in the quantity of medication consumed, time to relapse, well being or treatment satisfaction. CONCLUSION: Symptom-triggered self-medication was as safe as fixed-schedule medication in treating outpatients with AD and mild to moderate symptoms of AWS. The SAWS is a powerful monitoring tool, because it is brief and permits the subject to log the withdrawal symptoms.

Reduction of fear-potentiated startle by benzodiazepines in C57BL/6J mice.

RATIONALE: Anxiety disorders affect 18% of the United States adult population annually. Recent surges in the diagnosis of posttraumatic stress disorder (PTSD) from combat-exposed veterans have prompted an urgent need to understand the pathophysiology underlying this debilitating condition. OBJECTIVES: Anxiety and fear responses are partly modulated by gamma aminobutyric acid type A (GABA(A)) receptor-mediated synaptic inhibition; benzodiazepines potentiate GABAergic inhibition and are effective anxiolytics. Many genetically modified mouse lines are generated and/or maintained on the C57BL/6J background, a strain where manipulation of anxiety-like behavior using benzodiazepines is difficult. Fear-potentiated startle (FPS), a test of conditioned fear, is a useful preclinical tool to study PTSD-like responses but has been difficult to establish in C57BL/6J mice. METHODS: We modified several FPS experimental parameters and developed a paradigm to assess conditioned fear in C57BL/6J mice. The 6-day protocol consisted of three startle Acclimation days, a Pre-Test day followed by Training and Testing for FPS. Subject responses to the effects of three benzodiazepines were also examined. RESULTS: C57BL/6J mice had low levels of unconditioned fear assessed during Pre-Test (15-18%) but showed robust FPS (80-120%) during the Test session. Conditioned fear responses extinguished over repeated test sessions. Administration of the benzodiazepines alprazolam (0.5 and 1 mg/kg, i.p.), chlordiazepoxide (5 and 10 mg/kg, i.p.), and diazepam (1, 2, and 4 mg/kg, i.p.) significantly reduced FPS to Pre-Test levels. CONCLUSIONS: We used a modified and pharmacologically-validated paradigm to assess FPS in mice thereby providing a powerful tool to examine the neurobiology of PTSD in genetic models of anxiety generated on the C57BL/6J background.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.

A prospective, randomized, trial of phenobarbital versus benzodiazepines for acute alcohol withdrawal.

OBJECTIVE: The aim of this study was to compare phenobarbital (PB) versus lorazepam (LZ) in the treatment of alcohol withdrawal in the emergency department (ED) and at 48 hours. METHODS: Prospectively, randomized, consenting patients were assessed using a modified Clinical Institute Withdrawal Assessment (CIWA) score and given intravenous PB (mean, 509 mg) or LZ (mean, 4.2 mg). At discharge, LZ patients received chlordiazepoxide (Librium), and PB patients received placebo. RESULTS: Of 44 patients, 25 received PB, and 19 LZ. Both PB and LZ reduced CIWA scores from baseline to discharge (15.0-5.4 and 16.8-4.2, P < .0001). There were no differences between PB and LZ in baseline CIWA scores (P = .3), discharge scores (P = .4), ED length of stay (267 versus 256 minutes, P = .8), admissions (12% versus 16%, P = .8), or 48-hour follow-up CIWA scores (5.8 versus 7.2, P = .6). CONCLUSION: Phenobarbital and LZ were similarly effective in the treatment of mild/moderate alcohol withdrawal in the ED and at 48 hours.

[Diagnostics and therapy of alcohol withdrawal syndrome: focus on delirium tremens and withdrawal seizure]. / Diagnostik und Therapie des Alkoholentzugssyndroms: Fokus auf Delirium tremens und Entzugskrampfanfall.

INTRODUCTION: Delirium tremens and withdrawal seizures are serious complications of an alcohol withdrawal syndrome. This review presents the diagnostic procedures required in case of the occurrence of a withdrawal seizure and delirium tremens as well as possible treatment options including prophylactic medication regimen for alcohol withdrawal syndrome. Furthermore non-pharmacological procedures accompanying delirium tremens and a potential integration of viewing videotapes of delirium tremens in the course of alcohol-specific therapy are discussed. METHODS: A systematic literature research using Pubmed has been carried out to find recent studies and review articles dealing with alcohol withdrawal syndrome. RESULTS AND DISCUSSION: Regarding the diagnostic algorithm in case of the occurrence of a withdrawal seizure or a delirium tremens basic diagnostic procedures and special diagnostics including neuro-imaging or cerebrospinal fluid puncture depending on patients' clinical condition have to be considered. Sedatives are important in treatment of alcohol withdrawal seizures and delirium tremens as well as in the prophylaxis of alcohol withdrawal syndrome. A long-lasting prescription of anticonvulsant medication in patients suffering from withdrawal seizure should be considered critically and can be carried out only under certain conditions.