Naloxone blocks the antianxiety but not the motor effects of benzodiazepines and pentobarbital: experimental studies and literature review

The role of opioid systems in the anticonflict effect of chlordiazepoxide, diazepam and pentobarbital was evaluated with a modified Vogel procedure. First, morphine, ineffective by itself, was combined with subeffective or marginally effective doses of the benzodiazepines in order to detect possible potentiation. However, the combined treatment reduced licking in the Vogel procedure as well as in a licking test where no shock was administered. Several doses of the benzodiazepines and pentobarbital were then administered in combination with several doses of the opiate antagonist naloxone. A dose-dependent inhibition of anticonflict effect was obtained. In an additional experiment, it was shown that naloxone blocked the effects of diazepam in the elevated plus-maze procedure. Motor deficiencies, as evaluated with a rotarod test, produced by the benzodiazepines and pentobarbital could not be antagonized by naloxone. It is concluded that opioids are important for the anticonflict but not for the motor effects of these drugs. An analysis of published studies concerning the interaction of opioids and benzodiazepines in several procedures supposed to reflect anxiolytic effects shows that the inhibition obtained with naloxone is reliable and not procedure specific. The mechanisms by which opiate antagonists produce this inhibition of anticonflict activity are not known. It is tentatively suggested that opioid activation associated with stress may be a necessary component of anxiolysis.Part of this study was presented at the Society for Neuroscience Annual Meeting, Washington DC, USA, November 7–12, 1993.     

Effects of adinazolam on plasma catecholamine, heart rate and blood pressure responses in stressed and non-stressed rats.

Adinazolam (ADI) is a new benzodiazepine with anxiolytic and antidepressant properties. To assess its effects on the acute stress response, rats were given a single intraperitoneal injection of 2.5 or 5.0 mg/kg of ADI and stressed for 1 hr by restraint. Neither dose of ADI had any effect on heart rate, blood pressure or norepinephrine (NE) and epinephrine (EP) in plasma in the resting rats. In the stressed animal, 2.5 and 5.0 mg/kg of ADI did not affect stress-induced increases in heart rate or blood pressure but both significantly reduced the stress-induced increases in plasma NE and EP. During certain stressful experiences in patients with abnormally-increased sympathetic drive, ADI may be therapeutically useful in reducing high levels of catecholamines.     

Pentobarbital attenuates stress-induced increases in noradrenaline release in specific brain regions of rats

To examine whether anxiolytic action of drugs acting at the GABA/BZD-chloride channel complex may be related to the brain noradrenergic system, we investigated the effect of pentobarbital, a typical barbiturate which has potent GABA modulating properties, on increased NA release in nine brain regions of stressed rats. Pentobarbital (10 and 25 mg/kg) was injected IP 65 min before sacrifice (5 min before one-hour immobilization stress). Levels of 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), the major metabolite of brain noradrenaline (NA), and of plasma corticosterone, were fluorometrically determined. Pentobarbital treatment by itself increased MHPG-SO4 levels in the thalamus, locus coeruleus (LC) region, midbrain and basal ganglia of nonstressed rats. Stress produced increases in MHPG-SO4 levels in all brain regions examined and elevation of plasma corticosterone levels. Pentobarbital attenuated, in a dose-dependent manner, stress-induced increases in MHPG-SO4 levels in the hypothalamus, thalamus, anterior cerebral cortex, LC region and basal ganglia and also attenuated the stress-induced elevation of plasma corticosterone levels. These data suggest that pentobarbital can attenuate both stress-induced increases in NA release in specific brain regions as well as activation of the hypothalamo-pituitary-adrenocortical system. These attenuating effects may be related to the anxiolytic action of barbiturates.     

Psychological stress-induced increases in noradrenaline release in rat brain regions are attenuated by diazepam, but not by morphine

By measuring levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4) in the hypothalamus, amygdala and locus coeruleus region, we investigated the effects of diazepam 5.0 mg/kg, morphine 6.0 mg/kg, or naloxone at 5.0 or 10 mg/kg injected SC immediately before stress exposure, on increases in NA release caused by psychological stress. Psychological stress, wherein rats were exposed to emotional responses which were displayed by other electrically shocked rats, significantly increased MHPG-SO4 levels in the three brain regions examined and elevated plasma corticosterone levels. Both increases in brain MHPG-SO4 levels and elevations of plasma corticosterone levels induced by stress were attenuated significantly by diazepam but neither by morphine nor by naloxone. MHPG-SO4 levels in the hypothalamus and amygdala in the morphine-stress group were significantly higher than those in the saline-stress group. These findings suggest that psychological stress, in which an emotional factor is predominantly involved, causes increases in NA release in these brain regions examined and that these increases are attenuated only by diazepam, in contrast to the previous report, where increases in brain NA release caused by immobilization stress are attenuated not only by diazepam but also by morphine and are enhanced by naloxone.     

Comparison of several benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies

This study compared the effects of the -carboline anxiolytic, abecarnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was related to the fraction of BZR occupied by the drug. Abecarnil was efficacious in both tests and showed anxiolytic effects comparable with alprazolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor activity suppressed by footshock (punished crossings). None of these compounds significantly altered non-punished crossings. In contrast, diazepam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20–60%). The number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor occupancy). Alpidem had very weak anxiolytic-like effects in this test and markedly reduced unpunished crossings at relatively low receptor occupancies (> 15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equal to that observed following diazepam or alprazolam administration. Bretazenil and ZK 95962 had weak effects on the measures of anxiolytic activity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries. The fractional BZR occupancies required to increase the time spent in the open arms of the maze to 250% of control levels were approximately 45% for abecarnil and alprazolam, 60% for diazepam, and 100% for ZK 95962. Bretazenil did not reach this potentiation at the doses tested (up to 89% receptor occupancy). Abecarnil appeared to act as a full agonist on the measures of anxiolytic activity in both tests (i.e. required low fractional BZR occupancies) but on the measures of stimulation or sedation was more similar to the BZR partial agonists (i.e. had no significant effects even at receptor occupancies approaching 100%). On this basis abecarnil could be described as a selective agonist. In general, the four-plate test was more sensitive than the plus-maze. For example, lower BZR occupancies were needed to produce significant anxiolytic effects in the four-plate test than in the plus-maze. In addition, the partial agonists bretazenil and ZK 95962, which both produced weak effects in the plus-maze, had similar anxiolytic potencies to the full BZR agonists, diazepam and alprazolam, in the four-plate test.     

Noradrenaline systems in the hypothalamus, amygdala and locus coeruleus are involved in the provocation of anxiety: basic studies

A variety of stressful events, including emotional stress, cause a marked increase in noradrenaline release in several brain regions, and especially in the hypothalamus, amygdala and locus coeruleus, in the rat brain. These findings suggest that an increased noradrenaline release could be closely related to the provocation of negative emotions such as anxiety and/or fear. In order to confirm this hypothesis, we carried out several studies. Diazepam, a typical benzodiazepine anxiolytic, significantly attenuated not only the immobilization stress-induced increase in noradrenaline release in the three rat brain regions but also the emotional changes of these animals, and these effects were antagonized by flumazenil, a benzodiazepine antagonist. Naloxone and opioid agents, such as morphine, beta-endorphin and [Met(5)]-enkephalin, significantly enhanced and attenuated the stress-induced increase in noradrenaline release in these regions and the stress-induced emotional change, respectively. Two stressful events which predominantly involve emotional factors, i.e., psychological stress and conditioned fear, caused significant increases in noradrenaline release selectively in these three brain regions and these increases were also significantly attenuated by pretreatment with diazepam in a flumazenil reversible manner. Yohimbine, an alpha(2)-adrenoceptor antagonist which caused a marked increase in noradrenaline release in the several brain regions, had an anxiolytic action in the two behavioral tests involving anxiety, i.e., the conditioned defensive burying test and the modified forced swim test. beta-Carbolines, which possess anxiogenic properties, significantly increased noradrenaline release in the hypothalamus, amygdala and locus coeruleus. Taken together, these findings suggest that the increased release of noradrenaline in the hypothalamus, amygdala and locus coeruleus is, in part, involved in the provocation of anxiety and/or fear in animals exposed to stress, and that the attenuation of this increase by benzodiazepine anxiolytics acting via the benzodiazepine receptor/GABAA receptor/chloride ionophore supramolecular complex may be the basic mechanism of action of these anxiolytic drugs.     

A double blind comparison of alprazolam,diazepam and placebo in the treatment of anxious out-patients

The anxiolytic effects of alprazolam, a triazolobenzodiazepine, were evaluated in a double-blind 28-day comparison with diazepam and placebo in 46 out-patients suffering from anxiety states of moderate to severe intensity. Alprazolam 1.5-3 mg per day was found to be of at least equivalent anxiolytic effect to 15-30 mg diazepam per day, and there was evidence of antidepressant activity by alprazolam, but not diazepam, in neurotic depression. Side-effects occurred least often with alprazolam and were minor in nature. Laboratory data showed no changes attributable to alprazolam even in a patient who swallowed 15 capsules (7.5 mg). It was concluded that alprazolam is a safe and effective anxiolytic which is well-tolerated and also shows some antidepressant activity.     

Development of differential tolerance to the sedative and anti-stress effects of benzodiazepines

Differential degree of tolerance has been reported to develop for anticonvulsant, sedative and skeletal muscle relaxant effects of benzodiazepines (BZDs). Acute treatment with BZDs reportedly reduces the formation of gastric stress ulcers and attenuates stress-induced immunosuppression. The present study investigates whether tolerance develops to these antistress effects of BZDs by using diazepam and chlordiazepoxide as representative drugs. A single dose of diazepam (5 mg/kg, i.p.) or chlordiazepoxide (20 mg/kg, i.p.) produced a significant reduction in locomotor activity, a measure of sedative effect and antagonized the effect of restraint stress (RS) on gastric mucosal lesions and anti-sheep red blood cell (SRBC) antibody titre. With chronic treatment (X 7 d), there was a marked tolerance to the sedative effect of both the studied BZD drugs, while much less tolerance developed to their ulcer protective action. However, no tolerance was observed to the attenuating effect of diazepam and chlordiazepoxide on RS-induced immunosuppression. Thus, the results of the present study indicate that different mechanisms may be involved in the development of tolerance to the sedative, antiulcer and immunomodulatory effects of BZDs.     

Alprazolam but not diazepam protects hamsters with heart disease from the medical consequences of stress

We have previously shown that subjecting cardiomyopathic hamsters in the lesion-developing period of their heart disease to cold-immobilization stress had lethal consequences which could be blocked by alprazolam treatment. This experiment replicated that finding and also examined the efficacy of diazepam in this paradigm. In contrast to alprazolam, diazepam did not prevent the cardiomyopathic subjects from succumbing to the stressor. Thus, the effect of alprazolam in reducing stress-induced mortality did not reflect a generic benzodiazepine action.     

<Emphasis Type="Italic">Saikokaryukotsuboreito</Emphasis>, a herbal medicine,prevents chronic stress-induced anxiety in rats: comparison with diazepam

Anxiety is frequently observed in several neuropsychiatric disorders, and stress is thought to precipitate or exacerbate anxiety. In this study, the anxiolytic action of a herbal medicine, saikokaryukotsuboreito, (SRBT) was examined in normal healthy rats using the elevated plus-maze test. Moreover, the improving effect of SRBT on chronic stress-induced anxiety was also examined. Single administration of SRBT did not have anxiolytic action in normal rats. Repeated administration of SRBT significantly improved chronic stress-induced anxiety. On the other hand, single administration of a typical anxiolytic, diazepam, had anxiolytic action in normal rats but repeated administration did not improve chronic stress-induced anxiety. These results suggest that SRBT does not have anxiolytic activity equivalent to that of diazepam but has potency for improving stress-related anxiety. This finding provides information important for the treatment of anxiety.     

喀什地区2家医院常用镇静催眠药应用分析

目的:调查分析喀什地区2家医院精神障碍患者镇静催眠药的应用情况,促进临床合理用药。方法:调取喀什地区2家医院计算机数据库中2010-2012年有关镇静催眠药的处方,对其品种、销售金额、用量、用药天数等进行统计、分析。结果:镇静催眠药销售金额逐年增加,2012年的增长率为23.63%;氟硝西泮销售金额排序居前列,且增幅最大;使用金额分列第2、3位的为阿普唑仑、劳拉西泮;中成药中,天王补心丸的销售金额逐年增加;用药频度(DDDs)排序前5位的为阿普唑仑、氟硝西泮、艾司唑仑、劳拉西泮、地西泮,除阿普唑仑[药物利用指数(DUI)=1.04]外其余药物DUI均<1。结论:喀什地区镇静催眠药使用较多的均为国家基本药物,临床应用较为合理,但加强管理仍十分必要。     

The selective serotonin (5-HT)1A receptor ligand, S15535, displays anxiolytic-like effects in the social interaction and Vogel models and suppresses dialysate levels of 5-HT in the dorsal hippocampus of freely-moving rats

RATIONALE: The benzodioxane, S15535, possesses low intrinsic activity and marked selectivity at 5-HT1A receptors, hippocampal populations of which are implicated in anxious states. OBJECTIVE: Herein, we examined its potential anxiolytic actions in relation to its influence upon extracellular levels of 5-HT in the dorsal hippocampus of freely-moving rats. Its effects were compared with those of other anxiolytic agents: the 5-HT1A agonists, buspirone and 8-hydroxy-2-(di-n-propylamino)-tetralin HBr (8-OH-DPAT), the 5-HT2C antagonist, SB206,553 and the benzodiazepine, diazepam. METHODS: Potential anxiolytic actions were evaluated in the Vogel conflict paradigm (increase in punished responses) and the social interaction (SI) test (increase in active SI) in rats. Extracellular levels of 5-HT were determined by microdialysis. RESULTS: In analogy to diazepam. S15535 increased punished responses in the Vogel test. This action was dose dependently expressed over a broad (16-fold) dose range. Buspirone and 8-OH-DPAT were likewise active, but yielded highly biphasic dose-response curves. SB206,553 was dose dependently active in this model. In the SI test, S15535 similarly mimicked the anxiolytic-like effect of diazepam and was active over a broad dose range. Buspirone and 8-OH-DPAT again showed biphasic dose-response curves, as did SB206,553. In both the Vogel and SI tests, the anxiolytic-like effects of S15535 were abolished by the selective 5-HT1A receptor antagonist, WAY100,635, which was inactive alone. S15535 exerted its anxiolytic-like effects with a more pronounced separation to motor-disruptive doses than the other drugs. Finally, S15535 suppressed dialysate levels of 5-HT in the dorsal hippocampus, an action abolished by WAY100,635. Buspirone, 8-OH-DPAT and diazepam, but not SB206,553, also reduced 5-HT levels. CONCLUSION: Likely reflecting its distinctive ability to selectively and preferentially activate pre- versus postsynaptic 5-HT1A receptors, S15535 suppresses hippocampal 5-HT release and displays marked anxiolytic-like effects over a broad dose range in the relative absence of motor perturbation.     

The effects of perinatal diazepam exposure on stress-induced activation of the mesotelencephalic dopamine system

The effects of perinatal diazepam exposure of rats on stress-induced metabolic activation of the mesotelencephalic dopamine (DA) system were examined. Footshock stress parameters were selected such that DA turnover was increased in the prefrontal cortex and certain mesolimbic dopaminergic regions; a stress-induced activation of striatum was not observed. Perinatal treatment with the anxiolytic benzodiazepine diazepam (days E8 through the first week after gestation) did not alter basal dopamine turnover in the prefrontal cortex or striatum, or in any of the mesolimbic sites examined except for the nucleus accumbens and ventral tegmental area (in which turnover was decreased). However, perinatal exposure to diazepam significantly reduced the magnitude of the stress-elicited increase in prefrontal cortical dopamine turnover, and conversely resulted in a stress-induced enhancement of turnover in the striatum. These data suggest that although perinatal exposure to diazepam may alter basal dopaminergic function in some regions, certain enduring changes in dopamine function in other mesotelencephalic DA sites are revealed only under conditions that result in perturbation of central dopamine neurons, such as environmental stress. These data also suggest that perinatal benzodiazepine exposure may be reflected in the adult in a decreased ability to cope with stress.     

Comparative Study of the Abuse Liability of Alprazolam,Lorazepam, Diazepam,Methaqualone, and Placebo

Subjective effects of two benzodiazepines–alprazolam and lorazepam– were compared with two drugs of known abuse potential–diazepam and methaqualone–and placebo. This double-blind, crossover trial tested 30 casual recreational sedative users in a seminaturalistic setting. Methaqualone was more euphoriant and less sedative than the benzodiazepines. Diazepam and lorazepam were more euphoriant than placebo; alprazolam's euphoriant effect did not differ from these treatments. On other measures of abuse liability the benzodiazepines rated similarly, diazepam rating highest.     

Antidepressant and anxiolytic effects of alprazolam versus the conventional antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats.

The antidepressant and anxiolytic effects of alprazolam were compared to those of desipramine, diazepam and buspirone in the forced swim test. Subchronic alprazolam induced a reduction in immobility similar to that of desipramine in 'non-pretested' and 'pretested' rats. In 'non-pretested' rats, the anti-immobility effect of desipramine was potentiated by diazepam and alprazolam, given before subchronic desipramine, while the anti-immobility effect of subchronic alprazolam was counteracted by diazepam. Diazepam, administered before the pretest session, counteracted, 24 h later, the anti-immobility effect of subchronic desipramine and alprazolam; alprazolam counteracted the anti-immobility effect of alprazolam but not of desipramine, buspirone at the highest doses tested potentiated the anti-immobility effect of subchronic desipramine but not of alprazolam. These data provide further support for the hypothesis that the GABA/benzodiazepine/Cl complex is directly implicated in the action of antidepressants and that systems other than the GABA system are involved in the antidepressant and anxiolytic effects of alprazolam.     

Eszopiclone stimulates the hypothalamo-pituitary-adrenal axis in the rat

Eszopiclone (Lunesta?) is used for the treatment of insomnia. It is the S (+)-enantiomer of racemic zopiclone, a cyclopyrrolone with no structural similarity to the hypnotic drugs zolpidem and zaleplon or to the benzodiazepines and barbiturates. Although eszopiclone interacts with the gamma-aminobutyric acid A-type (GABA(A)) receptor complex, it has a different binding profile than other sedative/hypnotic agents and modulates the receptor complex in a unique manner. Thus, eszopiclone might produce different pharmacological effects compared to other sedative/hypnotic agents. Beside their behavioral properties, sedative/hypnotic drugs affect the hypothalamo-pituitary-adrenal (HPA) axis. In general, low doses of benzodiazepine-type drugs decrease, whereas high doses increase the activity of the HPA axis. Furthermore, benzodiazepines reduce stress-induced increases in HPA axis activity. The goal of the present study was to characterize the effects of eszopiclone on the HPA axis in the rat. Male rats were injected with saline or eszopiclone and trunk blood was collected for the measurement of plasma levels of adrenocorticotropin (ACTH) and corticosterone by radioimmunoassay. The acute administration of eszopiclone produced dose-dependent increases in plasma levels of ACTH and corticosterone, and tolerance developed to these effects after repeated drug administration. Pretreatment with eszopiclone did not affect stress-induced stimulation of the HPA axis. These results show that eszopiclone and the benzodiazepine-type drugs differentially affect the HPA axis.     

Effects of mental and physical stress on plasma catecholamine levels before and afterβ-adrenoceptor blocker treatment

Summary In a study in mild hypertensives, the impact of mental and physical stress on plasma epinephrine (E), norepinephrine (NE), and on their ratio (NE/E) was evaluated. The effect of two-adrenoceptor blocking drugs, atenolol and bopindolol, on plasma catecholamine levels was also examined.Each stressful stimulus significantly increased the NE and E levels compared to rest. The increase was progressive from mental stress, through the handgrip test to the treadmill test. A slight decrease in the NE/E ratio was observed following mental stress and the handgrip test, while this ratio increased during the treadmill test.No significant impact of beta blocking treatment on catecholamine levels was observed under any test condition.     

Isobolographic analysis of the sedative interaction between six central nervous system depressant drugs and Valeriana edulis hydroalcoholic extract in mice

It has been declared frequently that valerian may potentiate the effect of other central nervous system (CNS) depressant drugs, however there has been a lack of experimental data. We have evaluated the profile of the interactions between the ethanol extract of Valeriana edulis spp procera and six CNS depressant drugs using an exploratory model to test the sedative effect in mice. All the compounds tested showed a dose-dependent sedative effect with the following ED50 values: valerian 181.62, diazepam 1.21, ethanol 1938, pentobarbital 11.86, buspirone 1.04, haloperidol 0.41 and diphenhydramine 17.06 mg kg-1. An isobolographic analysis was used to evaluate the sedative interaction of the intraperitoneal co-administration of 1:1 fixed-ratio combination of equi-effective doses of valerian extract with each CNS depressant drug. The ED50 theoretical (Zadd) and experimental (Zexp) for each combination were: valerian+diazepam,Zadd=91.41 mg kg-1, Zexp=81.64 mg kg-1; valerian+ethanol, Zadd=1060.22 mg kg-1, Zexp=687.89 mg kg-1; valerian+pentobarbital, Zadd=96.74 mg kg-1, Zexp=151.83 mg kg-1; valerian+buspirone, Zadd=91.33 mg kg-1, Zexp=112.73 mg kg-1; valerian+haloperidol, Zadd=91.01 mg kg-1, Zexp=91.52 mg kg-1; valerian+diphenhydramine, Zadd=99.34 mg kg-1, Zexp=123.52 mg kg-1. Neither synergistic nor attenuate effects were found in any of the combinations evaluated. We concluded that the valerian extract did not potentiate the sedative effect of commonly prescribed CNS depressant drugs as was expected. The additive effect found through the isobolographic analysis suggested that the sedative effect of V. edulis resulted from the activation of common mechanisms of haloperidol, diazepam, buspirone, pentobarbital, diphenhydramine and ethanol.     

Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action

Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.     

GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knockout mice on a 129/Sv background

Previous studies in 5-HT(1A) receptor knockout (1AKO) mice on a mixed Swiss Websterx129/Sv (SWx129/Sv) and a pure 129/Sv genetic background suggest a differential gamma-aminobutyric acid (GABA(A))-benzodiazepine receptor complex sensitivity in both strains, independent from the anxious phenotype. To further investigate these discrepancies, various GABA(A)-benzodiazepine receptor ligands were tested in different behavioral paradigms in 1AKO and wild type (WT) mice on a 129/Sv background. 1AKO and WT mice responded comparably to alprazolam, flumazenil, alcohol and pentylenetetrazol as measured in the stress-induced hyperthermia paradigm. In addition, sedative-anesthetic effects of pentobarbital measured via the righting reflex were similar and a selected dose of diazepam exerted similar anxiolytic effects in both genotypes in the elevated plus maze. In conclusion, 1AKO mice on a 129/Sv background have undisturbed GABA(A)-benzodiazepine receptor sensitivity in contrast to those described on a mixed Swiss Websterx129/Sv background. The anxious phenotype of 1AKO mice seems to occur independent of the GABA(A)-benzodiazepine receptor complex functioning.