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PubMed2001

Effect of diazepam on the contents of amino acids and free radical during ischemia/reperfusion injury.

The protective effect and mechanism of diazepam on ischemia neurons during cerebral ischemia and reperfusion were studied. Sixty-three Wistar rats were divided randomly into nine groups: control group (n = 7), ischemia (is) groups including subgroups of is3 h, is3-h/rep1-h, is3-h/rep2-h, is3-h/rep3-h(n = 7 in each group), diazepam treated groups (10 mg/kg, i.p.), including subgroups of is3-h, is3-h/rep1-h, is3-h/rep2-h, is3-h/rep3-h (n = 7 in each group) with Zea longa's animal model of middle cerebral artery occlusion. The comparison between the ischemia group and diazepam-treated group showed that diazepam could obviously decrease the production of glutamate, asparate, MDA and increase the synthesis and release of GABA, SOD and GSH-PX. It was concluded that diazepam exerted its protective effects on neurons through complex mechanisms of regulating the synthesis and release of excitotary/inhibitory amino acids and free radicals.

Amino Acids↗
PubMed1998

Deafness and prolonged neuromuscular blockade following single-dose peritoneal neomycin irrigation.

PURPOSE: A case of deafness is reported in a patient undergoing bilateral nephrectomy after single irrigation of the peritoneal cavity with a neomycin containing solution for surgical prophylaxis. CLINICAL FEATURES: In this patient, profound, late-postoperative deafness was heralded by prolonged neuromuscular blockade and respiratory insufficiency. Additional risk factors for ototoxicity in this particular patient included the presence of end-stage renal disease requiring daily peritoneal dialysis and, possibly, the concomitant use of clonazepam and clindamycin. CONCLUSIONS: Antibiotic irrigation solutions containing neomycin may produce unwanted adverse systemic effects of deafness and prolonged neuromuscular blockade, even with only brief application within the peritoneal cavity. Concurrent end-stage renal disease, visceral inflammation from chronic dialysis and laparotomy, and the concomitant use of other medications may have contributed to these unwanted effects.

Anti-Bacterial Agents↗
PubMed1999

Effects of ketamine and pentobarbital on noradrenaline release from the medial prefrontal cortex in rats.

PURPOSE: To determine the effects of ketamine and pentobarbital on noradrenaline release from the medial prefrontal cortex. METHODS: In 14 male Wistar rats, a microdialysis probe with a 2 mm long semipermeable membrane was implanted in the medial prefrontal cortex. The dialysis probe was perfused at a rate of 1 microl x min(-1) with an artificial cerebrospinal fluid solution. The rats were randomly allocated to two groups: ketamine (group K, n=7) and pentobarbital (group P, n=7). Each rat was subsequently given 0 (saline), 1, 10 and 100 mg x kg(-1) ketamine i.p. in group K, and 0 (saline), 0.5, 5 and 50 mg x kg(-1) pentobarbital i.p. in group P. Sixty minutes elapsed between administration. Noradrenaline concentration was measured by HPLC with an electrochemical detector at 20 min intervals. (detection limit: 250 fg x 20 microl(-1), coefficient variation of the assay: 4.9%). The data in the 20-40 min after each dose of ketamine or pentobarbital i.p. were used for the statistical analysis. RESULTS: Noradrenaline release after 100 mg x kg(-1) ketamine increased by 7.7 +/- 2.0 (SEM) pg x collection(-1) compared with 2.7 +/- 0.7, 3.3 +/- 1.0 and 4.2 +/- 0.8 pg x collection(-1) after saline, 1 and 10 mg x kg(-1) ketamine, respectively (P < 0.05). Noradrenaline release did not change after pentobarbital. CONCLUSION: This study suggests the ketamine and pentobarbital have different effects on noradrenergic neurons in the medial prefrontal cortex. The stimulating effect of ketamine on noradrenaline release from the cortex might contribute to unique clinical features of ketamine anesthesia.

Adjuvants, Anesthesia↗
PubMed2000

Plasma concentration of flumazenil following intranasal administration in children.

PURPOSE: A pharmacokinetic study in children to determine plasma flumazenil concentrations after the intranasal administration of 40 microg x kg(-1). METHODS: Following institutional approval and informed written consent, 11 ASA physical status I-II patients, aged two to six years, undergoing general anesthesia for dental surgery were recruited. After induction, 40 microg x kg(-1) flumazenil Anexate, Roche, 0.1 mg x mL(-1) (0.4 mL x kg(-1))) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t = 0), and then at 2, 4, 6, 8, 10, 15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the on-site laboratory and then stored at -70 degrees C, before batch analysis via high performance liquid chromatography assay. Pharmacokinetic data calculations were performed using WinNonLin software (Scientific Consulting Inc.). RESULTS: Eleven patients were studied, but data for one patient were discarded due to insufficient sampling. The median age was 4.3 yr (range 3 to 6), with a median weight of 18.9 kg (range 14.9 to 22.2). There were seven boys and three girls. Mean Cmax was 67.8 ng x mL(-1) (SD 41.9), with Tmax at two minutes. The calculated half-life was 122 min (SD 99). CONCLUSION: The mean plasma concentrations of flumazenil attained were similar to those reported after intravenous administration, and may be sufficient to antagonize the side-effects of benzodiazepines. This route of administration may be useful when the intravenous route is not readily available.

Administration, Intranasal↗
PubMed1997

Midazolam reverses histamine-induced bronchoconstriction in dogs.

PURPOSE: Midazolam has been used clinically as a sedative and as an anaesthetic induction agent. However, the bronchodilating effects of midazolam have not been comprehensively evaluated. We sought to determine relaxant effects of midazolam on the airway. METHODS: After our Animal Care Committee approved the study, eight mongrel dogs were anaesthetized with 30 mg.kg-1 pentobarbitone iv, and were paralysed with 200 micrograms.kg-1.hr-1 pancuronium. The trachea was intubated with an endotracheal tube (ID 7 mm) that had a second lumen for insertion of a superfine fibreoptic bronchoscope (OD 2.2 mm) to measure the bronchial cross-sectional area (BCA) continuously. The tip of the bronchoscope was placed at the level of the second or third bronchial bifurcation of the right bronchus. A videoprinter printed the BCA which was then measured with a NIH image program. Bronchoconstriction was produced with histamine (H) 10 micrograms.kg-1 followed by 500 micrograms.kg-1.hr-1. Thirty minutes later, 0 [saline], 0.01, 0.1 and 1.0 mg.kg-1 midazolam and 25 micrograms.kg-1 flumazenil were given. The BCA was assessed before (basal area) and 30 min after the start of H infusion, and was also measured five minutes after each midazolam and flumazenil iv. At the same time, arterial blood was sampled for plasma catecholamine measurement. RESULTS: Histamine infusion decreased BCA to 49.7 +/- 17.3% of basal BCA. More than 0.1 mg.kg-1 midazolam increased BCA up to 71.7 +/- 15.3% of the basal (1.0 mg.kg-1) (P < 0.01). Plasma adrenaline concentration was decreased from 6.9 +/- 3.8 to 3.7 +/- 1.9 ng.ml-1 by 1.0 mg.kg-1 midazolam (P < 0.05). Flumazenil did not antagonize the relaxant effect of midazolam but reversed the inhibitory effect of midazolam on histamine-induced adrenaline release. CONCLUSION: Midazolam has a spasmolytic effect on constricted airways but this bronchodilatation was not reversed by flumazenil.

Anesthetics, Intravenous↗
PubMed2006

Effect of thiopental sodium on N-methyl-D-aspartate-gated currents.

PURPOSE: N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC) are closely related with the excitability of pyramidal neurons and PFC function. As the effect of thiopental sodium on the central nervous system may partly result from the inhibition of PFC NMDA receptors, we investigated the effect of thiopental sodium with different concentrations on NMDA-gated currents in acutely dissociated rat PFC pyramidal neurons. We sought to determine whether thiopental sodium inhibits NMDA receptor function. METHODS: Three to four week old male Sprague-Dawley rats were sacrificed and the PFC was dissected. Pyramidal neurons from the PFC were prepared and standard whole-cell patch clamp recordings were performed. Escalating concentrations from 3-1000 microM NMDA were applied 100 microm from the pyramidal cells, and the concentration in the effect compartment related to 50% effect (EC50) of NMDA was determined for the ensuing experiments. One hundred microM NMDA alone (control) or NMDA with different concentrations (10-1000 microM) of thiopental sodium were applied. After the inhibitory concentration, in 50% of NMDA effect (IC50) of thiopental sodium was established this IC50 and NMDA 3-1000 microM were applied 100 microm from the pyramidal cells. The EC50 value of NMDA under the effect of IC50 thiopental sodium was determined. RESULTS: N-methyl-D-aspartate induced inward currents in a concentration-dependent manner, which were completely antagonized by 50 microM AP5. The maximal amplitude of NMDA-induced current was 1.15 +/- 0.27 nA. The EC50 of NMDA was 53.6 +/- 12.4 microM. The NMDA (100 microM)-gated current was inhibited by thiopental sodium in a concentration-dependent manner, and the IC50 of thiopental sodium was 33.6 +/- 6.1 microM. Under the effect of 33.6 microM thiopental sodium, the maximal amplitude of NMDA-induced current was 0.87 +/- 0.17 nA. The concentration-response curve of NMDA was shifted rightwards. The EC50 of NMDA was 128 +/- 15 microM, which was greater than that of NMDA without thiopental sodium (P < 0.01). CONCLUSIONS: Thiopental sodium decreases NMDA-gated currents in acutely dissociated rat prefrontal cortical pyramidal neurons in a concentration-dependent manner.

2-Amino-5-phosphonovalerate↗
PubMed2002

Alprazolam, a benzodiazepine, does not modify the ACTH and cortisol response to hCRH and AVP, but blunts the cortisol response to ACTH in humans.

Alprazolam (AL), a benzodiazepine which activates gamma-amino butyrric acid (GABA)-ergic receptors, exerts a clear inhibitory effect on the activity of the hypothalamo-pituitary-adrenal (HPA) axis and is able to markedly reduce the ACTH response to metyrapone-induced inhibition of glucocorticoid feedback. It has been suggested that its inhibitory action could be regulated by CRH or AVP mediated mechanisms. However, the effect of benzodiazepines on the HPA response to CRH or AVP is contradictory. It has been shown that benzodiazepines have specific receptors on the adrenal gland but it is unclear if they mediate biological effects in humans. In order to further clarify the mechanisms underlying the inhibitory effect of benzodiazepine on HPA axis in humans, we studied the effect of AL (0.02 mg/kg po at -90 min) or placebo in 7 healthy young volunteers (7 female, age: 26-34 yr; wt: 50-58 kg, BMI 20-22 kg/m2) on: 1) the ACTH and cortisol responses to hCRH (2.0 microg/kg iv at 0 min) or AVP (0.17 U/kg im at 0 min); 2) the cortisol, aldosterone and DHEA responses to ACTH 1-24 (0.06 and 250 microg iv at 0 and 60 min, respectively). After placebo, the ACTH and cortisol responses to hCRH (peaks, mean+/-SE: 29.8+/-4.4 pg/ml and 199.3+/-19.6 microg/l) were similar to those recorded after AVP (31.7+/-6.5 pg/ml and 164.8+/-18.0 microg/l); the cortisol response to 0.06 microg ACTH (190.4+/-11.8 microg/l) was similar to that recorded after hCRH and AVP but lower (p<0.01) than that after 250 microg ACTH (260.6+/-17.4 microg/l). AL did not modify the ACTH response to both hCRH (42.5+/-7.1 pg/ml) and AVP (33.3+/-2.7 pg/ml), which even showed a trend toward increase. AL also failed to significantly modify the cortisol response to both hCRH (156.3+/-12.7 microg/l) and AVP (119.4+/-14.5 microg/l), which, on the other hand, showed a trend toward decrease. The cortisol peaks after 0.06 microg ACTH were significantly reduced (p<0.02) by AL pre-treatment (115.0+/-7.7 microg/l) which, in turn, did not modify the cortisol response to the subsequent ACTH bolus (214.7+/-16.6 microg/l). The DHEA and aldosterone responses to all the ACTH doses were not significantly modified by AL. In conclusion, these data show that the HPA response to AVP as well as to hCRH is refractory to the inhibitory effect of AL which, in turn, blunts the cortisol response to low ACTH dose. These findings suggest that both CRH- and AVP-mediated mechanisms could underlie the CNS-mediated inhibitory effect of AL on HPA axis; in the meantime, these results suggest that benzodiazepines could also act on adrenal gland by blunting the sensitivity of the fasciculata zone to ACTH.

Adrenocorticotropic Hormone↗
PubMed2004

Response of the hypothalamic-pituitary-adrenal axis to small dose arginine-vasopressin and daily urinary free cortisol before and after alprazolam pre-treatment differs in obesity.

OBJECTIVE: Arginine vasopressin (AVP) has a central role in the response of the hypothalamic-pituitary-adrenal (HPA) axis to stress conditions. A low dose of AVP has been shown to have a modest, but significant effect on ACTH response in normal weight subjects. The aim of this study was to test the response of the HPA axis in obese subjects in order to assess eventual primary neuroendocrine alterations, previously demonstrated by using AVP combined with corticotropin releasing hormone (CRH). In addition, given its central inhibitory action on the HPA axis, we investigated whether the suppressive capacity of alprazolam (APZ) pretreatment on the hormone response to low-dose AVP challenge and daily urinary free cortisol (UFC) excretion rate may be altered in the presence of obesity. DESIGN: Fifteen overweight or obese women and eight normal-weight controls randomly underwent two low-dose AVP tests (0.3 UI iv bolus), one without (AVP test) and the other preceded by APZ administration (0.5 mg at midnight and 0.5 mg 90 min before the test in the morning at 08:30 h) (APZ/AVP test). Blood samples for ACTH and cortisol assay were obtained at baseline and throughout each test. The day before each test, 24h-UFC/ creatinine was also mea-sured. RESULTS: Basal ACTH levels were similar in the two groups, whereas cortisol concentrations were significantly lower in the overweight/obese group. Overweight/obese women had higher ACTH and cortisol responses to the AVP tests and significantly greater hormone inhibition after APZ than controls. In both groups, AVP-induced delta-peak cortisol values before and after APZ pre-treatment were significantly correlated. Body fat distribution had no effect on the HPA axis response to AVP either before or after APZ. Moreover, APZ decreased 24h-UFC/creatinine values unsignificantly in controls and by approximately 50% in the overweight/obese subjects. These changes were unrelated to the cortisol response to the AVP test before and after APZ pretreatment. On the other hand, percent changes of 24h-UFC/creatinine after APZ were negatively related to the body mass index (BMI) but positively with waist circumference values, which indicates that the abdominal obesity phenotype may counteract the 24 h-UFC/creatinine that would be expected on the basis of BMI values. CONCLUSIONS: Our data further support the concept that in women obesity may represent a condition of hyperresponsiveness or hypersensitivity of the HPA axis to neuroendocrine stimuli, which appear to be independent of feedback control. In addition, the data on the inhibiting capacity of APZ on UFC excretion confirm that the alterations of the HPA axis in obesity is particularly evident in the abdominal phenotype.

Adult↗
PubMed1999

Differences in agonist-independent activity of 5-Ht2A and 5-HT2c receptors revealed by heterologous expression.

5-Hydroxytryptamine 5-HT2A and 5-HT2C receptors share many properties, including a common ability to stimulate phospholipase C. Traditionally, this activation was thought to be initiated only after agonist binding, in accordance with the ternary complex model of receptor function. Recently, though, the 5-HT2C receptor was shown to deviate from this tenet by spontaneously isomerizing into the active receptor state, thereby activating G proteins in the absence of agonist. To determine if 5-HT2A receptors share this property of constitutive activity, 5-HT2A and 5-HT2C receptor function was evaluated in transiently transfected NIH 3T3 fibroblasts. In 3T3 cells expressing 5-HT2C receptors, agonist-independent phosphatidyl inositol hydrolysis was substantially elevated relative to mock-transfected cells. In contrast, expression of the 5-HT2A receptor at the same density caused only a marginal increase in basal signaling. Control experiments in the current and previous papers establish that basal activity does not reflect contaminating serotonin. In addition, the magnitude of serotonin-induced signaling was the same in cells expressing either receptor, suggesting that the intrinsic ability of the two receptors to couple to G proteins is comparable. These data indicate that the 5-HT2A receptor has a much lower intrinsic ability to spontaneously adopt or maintain the active receptor conformation than does the closely related 5-HT2C receptor.

3T3 Cells↗
PubMed2003

[Dissociative stupor as a postoperative consequence of general anesthesia].

A 31-year-old woman failed to awaken after an uneventful general anesthesia (propofol, alfentanil and 65% N2O in oxygen) for laparoscopic resection of an ovarian cyst. After the operation she was extubated and vital signs were stable. However, the patient remained unresponsive even to painful stimuli for about 2 h. Just before we performed a computed tomogram of the brain to exclude a cerebral lesion we noticed that she blinked. We hypothesized that unconsciousness was due to a dissociative stupor. After administration of sublingual lorazepam the patient woke up promptly and was alert and normal for the rest of the hospital stay. In conclusion, after exclusion of a pharmacological or organic cause for postoperative unconsciousness, dissociative stupor may be a reason for apparent coma after general anesthesia.

Adult↗
PubMed2001

Effects of fenfluramine, m-CPP and triazolam on repeated-acquisition in squirrel monkeys before and after neurotoxic MDMA administration.

RATIONALE: Establishing functional deficits as a result of neurotoxic dosing regimens of MDMA has been difficult. However, moderate success has been achieved when sensitive animal models and drug challenge have been used together. OBJECTIVE: The present study used a repeated-acquisition technique and dose-effect determinations before, during and after neurotoxic MDMA exposure to characterize the effects of serotonergic drugs on learning, and to determine if MDMA-induced serotonin (5-HT) neurotoxicity is associated with learning deficits as measured by changes in response rate or the percentage of errors. METHOD: The effects of various serotonergic drugs were characterized in six squirrel monkeys responding under a repeated-acquisition procedure before and after neurotoxic dose regimens of MDMA. Specifically, cumulative dose-effect curves for m-CPP (0.032-1 mg/kg), fenfluramine (0.1-3.2 mg/kg) and triazolam (0.0032-0.1 mg/kg) were obtained prior to MDMA administration, with the latter drug serving as a non-5-HT control. RESULTS: In general, all of the drugs tested decreased overall response rate as the cumulative dose increased, whereas only triazolam markedly increased the percentage of errors. MDMA treatment produced significant (80-99%) decreases in brain 5-HT and 5-HIAA axonal markers, but did not lead to changes in either dependent measure of responding or shifts in the dose-effect curves obtained during pharmacological challenges with m-CPP, fenfluramine or triazolam. CONCLUSIONS: Taken together, these results demonstrate that serotonergic drugs can disrupt learning in monkeys, but indicate that MDMA-induced 5-HT neurotoxicity does not lead to disruptions in this particular type of serial learning task.

Animals↗
PubMed2002

Effect of pentobarbital, d-amphetamine, and nicotine on two models of sustained attention in pigeons.

RATIONALE: The animal literature examining the effects of drugs of abuse on sustained attention has provided conflicting results. One reason for these inconsistencies could be the different type of tasks used to measure sustained attention. OBJECTIVE: Acute effects of pentobarbital (0.3, 1, 3, 5.6, 10, and 13 mg/kg), d-amphetamine (0.03, 0.1, 0.3, 1, 3, and 5.6 mg/kg), and nicotine (0.03, 0.1, 0.3, 1, and 3 mg/kg) were compared in two models of sustained attention. METHODS: Dose-response curves were compared in eight male, white Carneaux pigeons trained under a continuous-trial attention procedure and in six male, white Carneaux pigeons trained under a discrete-trial attention procedure. Both procedures required subjects to respond to a variable and brief signal presentation (signal was presented on average every 6.5 s). RESULTS: Under the continuous-trial procedure, pentobarbital decreased hits as well as increased the number of false alarms and misses at doses that did not impair the ability of the animals to respond. d-Amphetamine and nicotine dose dependently decreased hits and increased misses at doses that did not impair rates of responding. However, neither psychomotor stimulant caused a significant increase in false alarms. Under the discrete-trial procedure, pentobarbital, d-amphetamine, and nicotine decreased hits and correct rejections and increased misses and errors of omission. For the most part, these drug effects occurred at doses that increased the latencies of the animals to respond. When comparing drug effects between the continuous- and discrete-trial procedures, a difference in the false alarm rate was observed. CONCLUSIONS: The present study shows that the continuous-trial procedure was able to detect differences between drug classes that were not apparent under the discrete-trial procedure. Although the lack of a true measure of a false alarm rate continues to be a problem with the continuous-trial procedure, it may be an important procedure for studying the effects of pharmacological agents.

Adrenergic Agents↗
PubMed2002

Relation between discriminative and reinforcing effects of midazolam, pentobarbital, chlordiazepoxide, zolpidem, and imidazenil in baboons.

RATIONALE: If a psychoactive drug shares discriminative effects with one that maintains self-administration, it is often inferred that the test drug is likely to be self-administered and to have abuse liability. This presumed predictive relationship has not been studied directly, however. OBJECTIVE: To determine at the level of the individual subject (1) whether a novel drug dose that shares discriminative effects with a reinforcing drug dose also will serve as a reinforcer, and (2) whether the results of generalization tests for drugs pharmacologically similar to the training drug predict whether the test drugs will or will not be self-administered. METHODS: Baboons were trained to discriminate midazolam (0.32 mg/kg, IV) from saline and also under a schedule of IV drug reinforcement. At the beginning of a period of self-administration, the first self-injection was followed 10 min later by a drug discrimination test session. The baboon then had the opportunity to self-administer the same dose 24 h/day (3-h timeout after each injection). A second drug discrimination test followed the last self-injection of the condition. RESULTS: Zolpidem and imidazenil shared discriminative effects with midazolam. Zolpidem was reinforcing in all baboons, but imidazenil was not. Chlordiazepoxide partially shared discriminative effects with midazolam, and the rate of self-administration was low. Pentobarbital did not share discriminative effects with midazolam, but was reinforcing. For all drugs, some doses did not share discriminative effects with midazolam but were reinforcing. Generalization gradients from tests after the last self-injection were similar to those after the first self-injection. CONCLUSIONS: The discriminative effect of a drug in relation to a training drug of the same pharmacological class is not isomorphic with its reinforcing effectiveness.

Animals↗
PubMed2002

Effects of delta9-THC and WIN-55,212-2 on place preference in the water maze in rats.

RATIONALE: Cannabinoids such as delta(9)-tetrahydrocannabinol (delta(9)-THC) or WIN-55,212-2 (WIN-2) have psychoactive effects on cognition. As a result, the reinforcing properties of delta(9)-THC or WIN-2 may confound learning and memory tests with false negative results. It therefore seems advisable to assess the reinforcing properties of the drugs in the same behavioural model used for learning experiments. OBJECTIVE: We therefore developed conditioned place preference protocols in the open-field water maze and tested both delta(9)-THC (2 mg/kg) and WIN-2 (1 mg/kg and 3 mg/kg). Given that previous reports on cannabinoids have revealed conflicting data and that this was a novel behavioural test, we also tested the benzodiazepine receptor agonist diazepam (2.5 mg/kg). Some methodical refinements were appropriate in order to determine the behavioural strategy implemented by the animals. METHODS: All animals were injected intraperitoneally 30 min prior to training/testing. In experiment 1, male hooded Lister rats injected with drug were repeatedly placed on the drug-related platform and subsequently tested for place preference. In experiment 2, rats were trained to swim to the drug platform on drug days and to the vehicle platform on vehicle days. A series of probe trials was introduced to delineate what had been learned. Experiment 3 studied the effect of WIN-2 on spatial learning in the water maze. RESULTS: Neither WIN-2 nor delta(9)-THC induced place preference in the water maze. When trained in the swim procedure, however, WIN-2 was neutral, but Delta(9)-THC resulted in place aversion. Conversely, diazepam consistently produced place preference in both procedures. WIN-2 (3 mg/kg), however, produced a small learning deficit in the spatial water maze task. CONCLUSION: It appears that the reinforcing properties of delta(9)-THC and WIN-2 in the doses used here are different, despite them both being agonists at cannabinoid receptors within the central nervous system. The fact that delta(9)-THC may be aversively related to a particular context has implications for previous work reporting deficits in spatial learning.

Animals↗
PubMed2004

Effects of word frequency on recall memory following lorazepam, alcohol, and lorazepam alcohol interaction in healthy volunteers.

Free recall of words has been extensively used in psychopharmacology to assess the effects of CNS-active drugs on memory functions. However, there is a relative lack of information on the impact of word frequency on the subsequent recall of words following the administration of psychoactive drugs. The present double-blind, placebo-controlled, repeated-measures experiment used lorazepam and alcohol to test the effects of word frequency on immediate and delayed word recall in 24 healthy volunteers. One half of the words contained in the lists had a high frequency (HF) of occurrence and the remainder were of low frequency (LF). The results showed that LF words were more sensitive to memory impairment than HF words. However, the more accurate recall of HF words (with respect to LF words) was eliminated when a combination of lorazepam with alcohol was administered. These findings indicate that word frequency has a significant impact on memory and, as such, is a factor to be taken into account when using memory recall tasks to assess the effects of psychoactive drugs on memory.

Adolescent↗
PubMed2004

Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure.

RATIONALE: Parametric preclinical studies of the benzodiazepine antagonist flumazenil have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use. However, few parametric studies have been conducted in human participants. OBJECTIVE: This study was designed to assess the effect of duration of benzodiazepine exposure on the intensity of flumazenil-precipitated withdrawal in healthy volunteers. METHOD: Participants were randomly assigned to receive either oral diazepam (15 mg/70 kg; n=10) or placebo (n=8) capsules nightly for 28 days. Effects of flumazenil (1 mg/70 kg, intravenously administered) were assessed in challenge sessions conducted before capsule ingestion, and after 1, 7, 14, and 28 days of capsule ingestion. RESULTS: Flumazenil produced a profile of participant-rated effects consistent with benzodiazepine withdrawal that peaked immediately after completion of the 5-min flumazenil injection and rapidly dissipated thereafter. The magnitude of these effects was comparable after 7, 14, and 28 days of diazepam. Flumazenil also produced modest elevations in blood pressure and decreases in skin temperature in the diazepam group, both of which were sustained throughout the approximate 60-min session. CONCLUSIONS: These findings support previous human research studies indicating that flumazenil precipitates withdrawal after short chronic exposure to benzodiazepines and suggests that duration of exposure does not influence the intensity of withdrawal beyond the first week of exposure.

Administration, Oral↗