Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in healthy volunteers

Summary The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design.No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST.These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.Presented in part at the Nineteenth Annual Meeting of the American College of Clinical Pharmacology, Las Vegas, NV, November 4–8, 1990     

Comparison of adinazolam, amitriptyline, and diazepam in endogenous depressive inpatients exhibiting DST nonsuppression or abnormal contingent negative variation

Adinazolam, a triazolobenzodiazepine that has an action similar to antidepressants in several pharmacological tests, was compared with amitriptyline and diazepam in endogenous depressive inpatients exhibiting dexamethasone suppression test non-suppression and/or abnormal contingent negative variation. Three parallel groups of 22 patients received in double-blind conditions either adinazolam (60-90 mg/day), amitriptyline (150-225 mg/day), or diazepam (30-45 mg/day) over a 4-week period, with weekly assessments by the Hamilton Rating Scale for Depression. Results showed significant superiority of amitriptyline over diazepam on total Hamilton depression scores. On the endogenomorphy subscale, amitriptyline induced significantly better improvement than both diazepam and adinazolam, whereas both amitriptyline and adinazolam exhibited significantly better antidepressant efficacy on the core symptoms of depression. Moreover, the dropout rate for inefficacy after 2 weeks of treatment was higher in the diazepam group. Taken together, these findings suggest that adinazolam has an antidepressant efficacy intermediate between amitriptyline and diazepam. Adinazolam was, however, much better tolerated than amitriptyline, and produced significantly fewer anticholinergic side effects.     

Kinetics and dynamics of intravenous adinazolam, N-desmethyl adinazolam, and alprazolam in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam mesylate (10 mg), N-desmethyl adinazolam mesylate (NDMAD, 10 mg), and alprazolam (1 mg) were investigated in 9 healthy male subjects in a randomized, blinded, single-dose, 4-way crossover study. All drugs were intravenously infused over 30 minutes. Plasma adinazolam, NDMAD, and alprazolam concentrations, electroencephalographic (EEG) activity in the beta (12-30 Hz) range, performance on the Digit Symbol Substitution Test (DSST), and subjective measures of mood and sedation were monitored for 12 to 24 hours. Mean pharmacokinetic parameters for adinazolam, NDMAD, and alprazolam, respectively, were as follows: volume of distribution (L), 106, 100, and 77; elimination half-life (hours), 2.9, 2.8, and 14.6; and clearance (mL/min), 444, 321, and 84. More than 80% of the total infused adinazolam dose was converted to systemically appearing NDMAD. All 3 benzodiazepine agonists significantly increased beta EEG activity, with alprazolam showing the strongest agonist activity and adinazolam showing the weakest activity. Alprazolam and NDMAD significantly decreased DSST performance, whereas adinazolam had no effect relative to placebo. Adinazolam, NDMAD, and alprazolam all produced significant observer-rated sedation. Plots of EEG effect versus plasma alprazolam concentration demonstrated counterclockwise hysteresis, consistent with an effect site delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect site concentration was related to pharmacodynamic EEG effect via the sigmoid E(max) model, yielding an effect site equilibration half-life of 4.8 minutes. The exponential effect model described NDMAD pharmacokinetics and EEG pharmacodynamics. The relation of both alprazolam and NDMAD plasma concentrations to DSST performance could be described by a modified exponential model. Pharmacokinetic-dynamic modeling was not possible for adinazolam, as the data did not conform to any known concentration-effect model. Collectively, these results indicate that the benzodiazepine-like effects occurring after adinazolam administration are mediated by mainly NDMAD.     

Effect of food on the bioavailability of adinazolam from a sustained release formulation: effect of meal timing and lack of dose dumping

Food effects on adinazolam absorption from sustained release (SR) adinazolam mesylate tablets were assessed in 28 healthy male volunteers. Subjects received 15 mg SR tablets, 15 mg immediate release tablets, 15 mg oral solution, administered after an overnight fast, and 15 mg SR tablets after a high fat breakfast. Treatments were administered in a crossover design. Plasma adinazolam and N-desmethyladinazolam (NDMAD) concentrations were determined by HPLC. Adinazolam and NDMAD AUC values were unaffected by food. Cmax for SR tablets was increased 33 per cent and 18 per cent for adinazolam and NDMAD, respectively, when administered postprandially. Tmax occurred later in the fed state; no dose dumping was observed. Meal timing effects on adinazolam absorption from SR tablets were assessed in 24 healthy subjects, who received 30 mg SR tablets 1 h before, 0.5 h after, 2 h after a high fat meal, and in the fasted state. Postprandial administration had no effect on AUC, but resulted later and higher adinazolam and NDMAD Cmax. Differences in these values were less than 11 per cent. Administration of SR tablets before meals yielded Cmax and Tmax values which were similar to the fasted state. Results suggest that meal timing does not substantially affect adinazolam absorption from the SR tablet.     

Pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam after oral and intravenous dosing in healthy young and elderly volunteers.

The pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam were studied in 18 young subjects, from 21 to 36 years of age, and 18 elderly subjects, ranging in age from 65 to 76 years. Nine men and 9 women per age group were studied in a randomized three-way crossover design. Single doses of one 30-mg adinazolam mesylate sustained release tablet, one 30-mg immediate release tablet, and 15 mg of intravenous adinazolam mesylate were administered. Plasma adinazolam and N-desmethyladinazolam were determined by high-performance liquid chromatography, and psychomotor performance tests, including digit-symbol substitution and two card-sorting tasks, were performed. An effect index, defined as the maximal performance decrement divided by N-desmethyladinazolam maximum plasma concentration was calculated as a measure of sensitivity to these effects. Adinazolam oral and systemic clearances were reduced approximately 30% and 25%, respectively, in elderly volunteers. Adinazolam half-life was prolonged approximately 40% in the elderly after oral dosing. N-Desmethyladinazolam plasma concentrations and half-life were increased approximately 40% in elderly volunteers. Psychomotor performance decrements were observed following all treatments; decrements were lowest following sustained release tablets and intravenous adinazolam. Maximal performance decrements in elderly subjects were approximately twice those observed in young subjects. No significant influence of age on the effect index for digit-symbol substitution was evident. Effect indices for card-sorting tests were significantly higher in the elderly. Lower clearances of adinazolam and N-desmethyladinazolam are observed in elderly volunteers, and increased N-desmethyladinazolam levels contribute to increased psychomotor performance decrements in elderly subjects. Results also suggest that elderly subjects may be more sensitive to certain cognitive effects of N-desmethyladinazolam.     

Ranitidine does not alter adinazolam pharmacokinetics or pharmacodynamics.

Adinazolam is a triazolobenzodiazepine with anxiolytic and antidepressant activity. Adinazolam is metabolized extensively; the major metabolite, N-desmethyladinazolam (NDMAD), possesses significant pharmacologic activity. NDMAD is eliminated predominantly by renal excretion. Ranitidine, a histamine H2-receptor antagonist, is also excreted renally and may compete with NDMAD for renal secretion. The purpose of this study was to examine the effect of ranitidine on the pharmacokinetics and pharmacodynamics of adinazolam and NDMAD. In a randomized, cross-over study, 12 healthy male volunteers received 300 mg of ranitidine orally followed by 30 mg of adinazolam 1 hour later (treatment A), or adinazolam alone (treatment B). Pharmacodynamic alterations were assessed using card sorting, digit-symbol substitution, and short-term memory tests. Venous blood samples were obtained over 24 hours for analysis of adinazolam and NDMAD by high-performance liquid chromatography. Urine samples also were collected and analyzed for NDMAD. No significant difference in adinazolam oral clearance (1,149 vs. 1,135 ml/hr/kg) was noted between treatments (A vs. B, respectively). Furthermore, the renal clearance of NDMAD (196 vs. 198 ml/min) and the cumulative urinary excretion of NDMAD (% dose; 61.2 vs. 62.3) were not significantly different. Repeated-measures analysis of variance indicated no significant differences in psychomotor performance or short-term memory between treatments. Results suggest that ranitidine has no effect on adinazolam disposition, NDMAD renal clearance, or the central nervous system effects mediated by the drug.     

Adinazolam pharmacokinetics and behavioral effects following administration of 20–60 mg oral doses of its mesylate salt in healthy volunteers

The pharmacokinetics and pharmacodynamics of adinazolam were studied in 15 normal, healthy, non-obse volunteers. Placebo capsules and capsules containing 20, 40, and 60 mg adinazolam mesylate were administered as single oral doses in a randomized, 4-way crossover design. Plasma concentrations of adinazolam and mono-N-desmethyladinazolam (NDMAD) were determined by HPLC. Psychomotor performance and memory tests were performed and the degree of sedation assessed at designated times following drug administration. Adinazolam and NDMAD pharmacokinetics were linear throughout the dosage range studied. The ratio of NDMAD to adinazolam area under the curve was approximately 4:1. Dose-related decrements in psychomotor performance and memory were observed up to 8h after dosing (P<0.025 in all cases). Psychomotor performance decrements correlated more closely with NDMAD plasma concentrations than with adinazolam concentrations. These results suggest that NDMAD is responsible for a significant degree of the sedative and psychomotor effects observed after the administration of adinazolam.     

Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Influence of repeated administration of cimetidine on the pharmacokinetics and pharmacodynamics of adinazolam in healthy subjects

Summary Adinazolam is a new triazolobenzodiazepine bearing an alkyl-amino side chain. A cross-over double-blind placebo controlled study was carried out in 12 healthy volunteers, in order to check the possible interaction between cimetidine and adinazolam after repeated co-administration.Cimetidine or placebo were given during 17 days. Beginning on Day 8 of each treatment, adinazolam was given in the increasing doses following sequence of doses for 3 days: 10 mg b.i.d., 20 mg b.i.d. and 20 mg t.i.d. A pharmacokinetic and pharmacodynamic study was performed on the third day at each dose. A wash-out of three weeks was included between the two treatments.Cimetidine increased significantly the AUC values of both adinazolam and N-desmethyladinazolam, reduced the oral clearance of adinazolam, and prolonged adinazolam's half-life.The digit symbol substitution test was significantly affected at each dose level while the manual dexterity was marginally impaired by adinazolam plus cimetidine.Saftee-up interview and Clyde mood scale indicated an increased sedation under adinazolam plus cimetidine in four subjects.     

Effects of single doses of alprazolam and diazepam,alone and in combination with ethanol,on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

Summary Effects of alprazolam, alone and in combination with ethanol, on psychomotor and cognitive performance were studied in healthy male volunteers and compared to effects of diazepam. Alprazolam 2 mg produced relatively long-lasting impairments on tests of tracking, verbal and nonverbal information processing, and memory, and decreased blood pressure without a change in heart rate or plasma norepinephrine levels. Although ethanol consumption was demonstrated to produce additive decrements in performance on certain tasks, there was little evidence to support a synergistic effect. Alprazolam 2 mg was accompanied by increased selfreports of side effects, especially drowsiness. Low dose alprazolam, diazepam, and ethanol produced significantly fewer side effects than 2 mg alprazolam, but significantly more than placebo.     

Adinazolam--a new antidepressant: findings of a placebo-controlled, double-blind study in outpatients with major depression

Adinazolam mesylate, a new triazolobenzodiazepine with antidepressant properties, was significantly superior to placebo based on the following efficacy measures: number of subjects who completed the study; number of subjects whose total score on the 21-item Hamilton Rating Scale for Depression (HAM-D) decreased by 50% or more; and number of subjects who reported that the drug helped them. Mean scores on three HAM-D clusters (anxiety/somatization, sleep disturbance, and an endogenomorphic cluster) also showed significant differences in favor of adinazolam. Side effects were generally mild and transient; however, a seizure of moderate intensity occurred during rapid tapering of adinazolam from 90 to 40 mg/day. There were no significant anticholinergic effects, and no mania or hypomania was reported in any subject. No consistently significant differences were observed between subjects whose primary diagnosis was major depression and those with a diagnosis of bipolar II depression.     

A controlled trial of adinazolam versus desipramine in geriatric depression

Thirty outpatients between the ages of 60 and 85 with DSM-III Major Depression entered an 8 week randomized, double-blind comparison of desipramine and adinazolam mesylate, a triazolobenzodiazepine derivative. Outcome was assessed on several measures including the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Rating Scale, Clinical Global Impressions (CGI), the 35-item Self-Rating Symptom Scale, and Carroll Depression Scale. Patients in both groups demonstrated a highly significant decrease in average HDRS scores (p less than 0.001) over the course of the study. Adinazolam was associated with significantly greater reduction in average HDRS scores by the third day. Repeated measures analysis of variance showed a significantly greater reduction in HDRS scores for adinazolam over the course of the study. The study medications were associated with distinct patterns of adverse reactions. Desipramine more often produced dry mouth, constipation and nervousness, while adinazolam was more likely to cause drowsiness and lightheadedness. Three of these elderly patients, all of whom were taking desipramine reported at least one fall during the study. Adinazolam may be a promising agent in the treatment of depression in the elderly.     

Effect of chronic administration of alprazolam and adinazolam on clonidine- or apomorphine-induced aggression in laboratory rodents

The activity of chronic (3 weeks) treatment with the triazolobenzodiazepines, alprazolam and adinazolam, on clonidine- and apomorphine-induced aggression were studied. Adinazolam, like desipramine, potentiated aggression induced by clonidine while diazepam and alprazolam completely abolished it. In the apomorphine-induced aggression, adinazolam suppressed both aggressivity and stereotypy, while diazepam slightly potentiated it. Alprazolam did not modify the effect of aggression induced by apomorphine. On the whole, while adinazolam seemed to develop an activity closer to that of a classical antidepressant like desipramine, alprazolam appeared to be more similar to the benzodiazepines on clonidine-induced aggression in mice. Compared to desipramine and diazepam, adinazolam left these two effects induced by apomorphine almost unchanged. The experiments performed showed differences between the profiles of action of the two triazolobenzodiazepines studied.     

Acute performance-impairing and subject-rated effects of triazolam and temazepam, alone and in combination with ethanol, in humans

The acute behavioural effects of triazolam (0.125 and 0.25 mg), temazepam (15 and 30 mg), and placebo, alone and in combination with ethanol (0 and 0.5 g/kg), were assessed in 10 volunteers. Ethanol alone did not impair performance and produced only a few subject-rated drug effects. Triazolam and temazepam alone produced some performance impairment and a few subject-rated drug effects. These effects tended to be dose-dependent and were comparable for the two drugs across the range of doses tested. The triazolam-ethanol and temazepam-ethanol combinations produced robust performance impairment and sedative-like subject-rated drug effects that were similar in magnitude. The findings of the present study suggest that even a moderate amount of ethanol in combination with a clinical dose of triazolam or temazepam can cause performance impairment that might diminish an individual's ability to respond adequately to unexpected demands (e.g. smoke alarms or middle-of-the-night child care).     

Kinetic Characterization and Identification of the Enzymes Responsible for the Hepatic Biotransformation of Adinazolam and N-Desmethyladinazolam in Man

The kinetics of the N-demethylation of adinazolam to N-desmethyladinazolam (NDMAD), and of NDMAD to didesmethyladinazolam (DDMAD), were studied with human liver microsomes using substrate concentrations in the range 10–1000 μm . The specific cytochrome P450 (CYP) isoforms mediating the biotransformations were identified using microsomes containing specific recombinant CYP isozymes expressed in human lympho-blastoid cells, and by the use of CYP isoform-selective chemical inhibitors. Adinazolam was demethylated by human liver microsomes to NDMAD, and NDMAD was demethylated to DDMAD; the substrate concentrations, K_m, at which the reaction velocities were 50% of the maximum were 92 and 259 μm , respectively. Another metabolite of yet undetermined identity (U) was also formed from NDMAD (K_m 498 μm ). Adinazolam was demethylated by cDNA-expressed CYP 2C19 (K_m 39 μm ) and CYP 3A4 (K_m 83 μm ); no detectable activity was observed for CYPs 1A2, 2C9, 2D6 and 2E1. Ketoconazole, a relatively specific CYP 3A4 inhibitor, inhibited the reaction; the concentration resulting in 50% of maximum inhibition, IC50, was 0·15 μm and the inhibition constant, K_i, was < 0·04 μm in five of six livers tested. Troleandomycin, a specific inhibitor of CYP 3A4, inhibited adinazolam N-demethylation with an IC50 of 1·96 μm . The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 μm ) and sulphaphenazole, α-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (K_m 220 μm , Hill number A 1·21), CYP 2C19 (K_m 187 μm , Hill number A 1·29) and CYP 2C9 (K_m 1068 μm ). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0·14 μm ) and formation of U (IC50 < 0·1 μm ) whereas omeprazole and sulphaphenazole had no effect on reaction rates. These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.     

Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release and Sustained-Release Adinazolam Mesylate Tablets After Single- and Multiple-Dose Administration

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on mulitiple dosing.     

N-desmethyladinazolam pharmacokinetics and behavioral effects following administration of 10–50 mg oral doses in healthy volunteers

Results of previous studies suggest that N-desmethyladinazolam, the major metabolite of adinazolam in man, contributes substantially to psychomotor effects and sedation observed following adinazolam administration. Therefore, the pharmacokinetics and pharmacodynamics of N-desmethyladinazolam were explored following administration of single oral doses of placebo and solutions containing 10, 30, and 50 mg N-desmethyladinazolam mesylate in a double-blind, randomized, four-way crossover design to 15 healthy male volunteers. Plasma concentrations of N-desmethyladinazolam were determined by HPLC. Psychomotor performance tests (digit symbol substitution and card sorting by fours and suits), memory tests and sedation scoring were also performed following drug administration. N-desmethyladinazolam pharmacokinetics were dose independent over this range. Doserelated performance effects were observed at 1, 2, and 6 h after dosing. Memory was likewise affected at 2 h. Psychomotor performance decrements correlated with log N-desmethyladinazolam plasma concentrations. Analysis of the relationship between percentage decrements in digit-symbol substitution and plasma N-desmethyladinazolam using the Hill equation revealed a EC₅₀ of 325 ng/ml. These results establish the relationship between N-desmethyladinazolam plasma concentrations and performance effects; these data will be helpful in assessing the contribution of N-desmethyladinazolam to clinical effects observed after adinazolam administration.     

Quercetin, a flavonoid antioxidant, prevents and protects against ethanol-induced oxidative stress in mouse liver

This study evaluates whether quercetin (25, 50 and 75 mg/kg body weight) treatment has a protective effect on the pro-oxidant-antioxidant state following chronic ethanol treatment in mice. Pretreatment (quercetin 25, 50 and 75 mg/kg body weight for 15 d+co-treatment of ethanol 18%+quercetin for 15 d and ethanol 18% for the 15 d) increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH) in comparison to the ethanol group. No significant differences from the ethanol group were observed in the group after post-treatment (ethanol 18% for 30 d+quercetin 25, 50 and 75 mg/kg body weight for 15 d) with quercetin. A significant increase in lipid peroxidation (malondialdehyde, MDA) products was observed in liver tissue after administration of ethanol, which was attenuated by pre- and post-treatment with a high dose of quercetin. GSH levels increased and oxidized glutathione (GSSG) levels decreased in groups of ethanol-exposed mice that received quercetin for 15 d prior to ethanol exposure. In conclusion, pre-treatment of quercetin may protect against ethanol-induced oxidative stress by directly quenching lipid peroxides and indirectly by enhancing the production of the endogenous antioxidant GSH. There was no protective effect on post-treatment with quercetin.     

Effects of ethanol and GABAB drugs on working memory in C57BL/6J and DBA/2J mice

RATIONALE: It has been suggested that GABA(B) receptors may be part of a neural substrate mediating some of the effects of ethanol. OBJECTIVE: The purpose of this experiment was to investigate, in mice, the effects of ethanol on working memory in a delayed matching-to position (DMTP) task, and additionally to determine if these effects were modulated by GABA(B) receptors. METHODS: Female C57BL/6J and DBA/2J mice were trained in the DMTP task, and after asymptotic levels of performance accuracy were achieved, injections (IP) of ethanol, baclofen, or phaclofen were administered. Baclofen or phaclofen were then co-administered with ethanol. Each test was repeated twice. RESULTS: Ethanol caused deficits in working memory at 2.0 g/kg and higher. The highest dose (2.5 g/kg) produced additional non-specific effects, indicative of sedation. Baclofen increased performance accuracy (2.5 mg/kg), while decreasing the total number of trials completed. When combined with ethanol (1.5 g/kg), baclofen increased memory deficits at the highest dose (7.5 mg/kg). Phaclofen increased performance accuracy at 10 and 30 mg/kg but had no effect on the total number of trials completed. When combined with ethanol (2.5 g/kg), phaclofen did not significantly alter ethanol-induced deficits in performance. CONCLUSIONS: Analyses of performance accuracy, total trials completed and variables indexing bias and motor impairment indicated that GABA(B) drugs modulate working memory in a behaviorally specific manner. Overall, these receptors may be part of a neural substrate that modulates some of the effects of ethanol.     

Neurobehavioral effect of triadimefon, a triazole fungicide, in male and female rats

Triadimefon is a widely used systemic fungicide, yet there is little published information on its effects in mammals. This study describes the effects of triadimefon in male and female rats using a functional observational battery (FOB), motor activity (measured in a figure-eight maze), and operant performance (responding under a fixed-interval 3-min schedule). For the FOB, Long-Evans hooded rats were tested immediately before dosing and 0.5, 4, 24, and 48 hr after IP dosing with either vehicle, 30, 100, or 300 mg/kg triadimefon. Prominent effects of triadimefon (100 and 300 mg/kg) included increased arousal, stereotypies involving repetitive sniffing, head bobbing, and pacing, and self-mutilation. Dose-related handling-induced convulsions, changes in reflexes and sensory reactivity, hypothermia, and body weight loss were also significant findings. Doses of 30, 75 and 150 mg/kg triadimefon increased figure-eight maze activity whereas 300 mg/kg decreased activity. Habituation of activity during the session as well as the spatial distribution within the maze were also affected by triadimefon. Overall rates of responding maintained by fixed-interval milk reinforcement were increased at 30 and 56 mg/kg, and decreased at 100 and 200 mg/kg. Responding within the 3-min fixed-interval was also affected, with low rates normally occurring early in the interval markedly increased. These effects on operant performance were similar to those seen following d-amphetamine, and were attenuated by pretreatment with chlorpromazine (0.5 mg/kg). On many measures, female rats appeared to be somewhat more sensitive than males. Recovery was evident in some measures the day after dosing, but the effects of high doses (greater than or equal to 100 mg/kg) were typically prolonged (several days). Thus triadimefon produced a unique neurotoxic syndrome which is similar in many aspects to that produced by CNS stimulants.