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PubMedDate not supplied

Diazepam enhances fentanyl and diminishes meperidine antinociception.

A rabbit tooth pulp antinociceptive model was used to investigate the effect of prior administration of diazepam or muscimol on the potency and duration of fentanyl and meperidine Potency experiments compared ED(50) values in all-or-none dose-response assays between both muscimol (0.25 mg/kg) and saline, and diazepam (1.5 mg/kg) and propylene glycol vehicle. An all-or-none effect was defined as doubling of voltage threshold to elicit a lick/chew evoked response. Duration experiments compared time (minutes) to 50% maximum possible effect (MPE) of an ED(90) dose of fentanyl (0.04 mg/kg) and to 50% and 20% MPE of an ED(98) dose of meperidine (17 mg/kg) 10 minutes after pretreatment with diazepam (1.5 mg/kg). Prior (10 minutes) injection of diazepam (1.5 mg/kg) increased the ED(50) value for meperidine (3.06 mg/kg) compared with its control (1.48 mg/kg), indicating a decrease in antinociceptive potency. The same dose of diazepam decreased the ED(50) value for fentanyl (1.1 μg/kg) compared with its control (13.1 μg/kg), indicating an increase in antinociceptive potency. Muscimol also had a similar effect on fentanyl (ED(50), 1.8 μg/kg) compared with saline control (ED(50), 13.8 μg/kg). Diazepam, vehicle, and muscimol by themselves had no effect on voltage thresholds to elicit a lick/chew response. Time to 50% MPE for diazepam-fentanyl was 38 minutes vs. 25 minutes for vehicle-fetanyl; time to 20% MPE for diazepam-meperidine was 38 minutes vs. 54 minutes for vehicle-meperidine (maximum percentage of MPE produced by diazepam-meperidine was 40% compared with 100% MPE for vehicle-meperidine). Percentages of MPE for diazepam-meperidine were significantly lower than those for vehicle-meperidine at all time intervals, whereas percentages of MPE for diazepam-fentanyl were significantly greater than those for vehicle-fentanyl over time.

Animals↗
PubMed1986

Effect of tubing length on adsorption of diazepam to polyvinyl chloride administration sets.

The effect of administration-set tubing length on adsorption of diazepam to polyvinyl chloride (PVC) tubing was studied, and a simple equation for calculating the dose of diazepam delivered to the patient during an i.v. infusion of diazepam was derived. Diazepam solutions were prepared in 500 mL of 0.9% sodium chloride injection in glass bottles to a final theoretical concentration of 50 micrograms/mL. PVC administration sets were attached to the bottles, and the tubing was then cut to various lengths or the entire length was used for infusion of diazepam solution at a constant rate of 60 mL/hr. Samples of the diazepam solution were collected in glass test tubes initially and after infusion periods of 0.25, 0.5, 0.75, 1.00, 1.50, 2.00, 3.00, and 4.00 hours. Diazepam concentrations were assayed spectrophotometrically in duplicate, and each infusion trial was performed three times. The mean diazepam concentrations in the bottles remained within 100 +/- 1% of initial concentration throughout the study. However, solution samples collected after the four-hour infusion period varied in concentration from 45.5 micrograms/mL using the 23-cm length of tubing to 28.8 micrograms/mL using the entire (185-cm) tubing. Also, the percentage of diazepam adsorbed to the tubing increased as the infusion time decreased. A biexponential equation based on the adsorption data obtained for various tubing lengths was successfully used to calculate the percentage of the theoretical diazepam dose delivered through the tubing during different infusion times. To minimize the adsorption of diazepam to PVC administration sets, the shortest possible length of administration-set tubing should be used.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1986

Effect of flow rate and type of i.v. container on adsorption of diazepam to i.v. administration systems.

The effect of flow rate and type of i.v. solution container on adsorption of diazepam to i.v. administration systems was studied. Diazepam solutions were prepared in 500 mL of 0.9% sodium chloride injection in glass, polyethylene, and polyvinyl chloride (PVC) containers to a final theoretical concentration of 50 micrograms/mL. PVC administration sets were attached to the containers, and diazepam solution was infused at flow rates of 30, 45, 60, 90, and 120 mL/hr. Solution samples were taken initially and at 0.25, 0.5, 0.75, 1.00, 1.50, 2.00, 3.00, and 4.00 hours after infusion of the first 5 mL of solution through the system. Three infusion trials were performed using each type of container. Adsorption of diazepam to each type of container was evaluated by serial measurements of diazepam concentration over a 168-hour period using five containers of each type. The effect of shaking the container on diazepam adsorption to PVC containers was tested by comparing concentrations in five containers that were shaken during a two-hour period with concentrations in five unshaken containers. Diazepam concentrations were measured spectrophotometrically in duplicate. Diazepam concentrations in glass containers remained unchanged throughout the 168-hour study period; concentrations decreased by about 5% in polyethylene containers and as much as 75% in PVC bags. Shaking increased diazepam adsorption to the PVC container. In the infusion trials, the percentage of diazepam adsorbed increased as flow rate decreased. The amount of diazepam adsorbed to the i.v. administration system was ore dependent on flow rate and infusion time than on the type of container used.(ABSTRACT TRUNCATED AT 250 WORDS)

Adsorption↗
PubMed1979

[Investigation on the influence of a tocolytic treatment of pregnant women with diazepam and fenoterol on the bilirubin levels and apgar score of newborn (author's transl)].

In a retrospective study of 2618 pregnant women we examined the influence of diazepam monotherapy as well as the combination of diazepam and fenoterol on the bilirubin concentrations and Apgar scores of the newborn children. In the diazepam-treated group 17-27% of the newborns showed Apgar scores of 6 or less. In the group treated with diazepam and fenoterol, 66-68% of the newborn had Apgar scores of 6 or less. The effect of diazepam on the bilirubin levels appears to depend on the dose and duration of the diazepam treatment: low, short term diazepam doses cause a slight bilirubin increase, while higher diazepam doses cause a reduction of the bilirubin levels. Following the combination therapy of diazepam and fenoterol a significant number of the infants developed neonatal jaundice. Due to the fact that following the combination therapy the diazepam concentration of the newborns were higher than following the monotherapy, we ascribe the greater frequency of the low Apgar values and also possibly the larger bilirubin increase to the higher diazepam concentration caused by fenoterol.

Apgar Score↗
PubMed1984

The influence of diazepam on the serum protein binding of bupivacaine at normal and acidic pH.

Since both bupivacaine and diazepam are highly protein bound, it is possible that a drug displacement interaction could occur, resulting in an increase in free bupivacaine concentration that could exacerbate systemic toxicity. This study was undertaken to characterize the serum binding of diazepam and to evaluate any drug displacement interaction between diazepam and bupivacaine. Human serum obtained from venous blood of normal male and female volunteers was used for measurements of protein binding using an Amicon Micropartition System. Bupivacaine protein binding in the presence of 0, 0.5 and 1.5 microgram/ml diazepam was best described by the model for two classes of binding sites. Neither concentration of diazepam significantly altered the capacity or affinity for either class of bupivacaine binding sites when compared to control. Free concentrations of bupivacaine were statistically identical in the presence of both diazepam concentrations. The complete diazepam binding profile in both serum and isolated human serum albumin was best described by a model describing two classes of binding sites. The effect of an acidic pH on bupivacaine was also independent of diazepam concentration. Diazepam protein binding was not affected by a reduction in pH from 7.4 to 7.0. The data reported here suggest no binding displacement interaction exists between bupivacaine and concomitantly administered diazepam. Thus, administration of diazepam during a toxic reaction associated with bupivacaine should not alter free bupivacaine concentration.

Acidosis↗
PubMed1995

Pharmacokinetic and pharmacodynamic evaluation of the potential drug interaction between venlafaxine and diazepam.

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two-period, crossover study was conducted in 18 men. Multiple-dose venlafaxine (50 mg every 8 hours) or placebo (double-blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single-blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O-desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 +/- 8 versus 26 +/- 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 +/- 0.28 versus 0.99 +/- 0.34 L/kg; P = .02), and AUC decreased (5973 +/- 2304 versus 5008 +/- 1354 ng.h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam-venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo-diazepam (37.85 +/- 3.28 Hz) and venlafaxine-diazepam (37.09 +/- 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.

Adult↗
PubMed1996

Pavlovian conditioning to a diazepam cue with yohimbine as the unconditional stimulus.

On multiple occasions, rats were administered diazepam (2.0 mg/kg, ip) followed 30 min thereafter by yohimbine hydrochloride (2.5 or 5. 0 mg/kg) or isotonic saline (forward conditioning groups). Three additional groups (backward conditioning controls) were given equivalent injections, but in reverse order. After eight such pairings, the effects of a single injection of diazepam on motor performance (balancing on a rotating drum) was assessed. Rats that had received either dose of yohimbine during forward conditioning trials maintained their balance longer than the saline controls. After four additional conditioning trials, the animals' activity patterns in a plus-maze screening test for anxiolytics were examined. Placed into the maze after a single test injection of isotonic saline, the behavior of all groups was virtually identical: less than 16% of total entries into or time spent in the four arms of the maze was spent in the two "open" arms (unprotected by surrounding walls). When tested in the maze again, but 35 min after a single injection of diazepam, the groups that had received diazepam but not yohimbine during the conditioning phase exhibited the expected increase in open-arm activity, and equivalent increases were found in backward conditioning groups. However, the group previously conditioned with 2.5 mg/kg of yohimbine following diazepam also showed an increased open-arm activity when tested with diazepam alone, but it was significantly greater than that seen in the control group. In contrast, the group conditioned with 5.0 mg/kg yohimbine following diazepam exhibited no effect of diazepam upon their plus maze activity; consequently, these animals spent less time in the open arms than either of the other groups. Yohimbine alone normally decreases open-arm activity (a putative "anxiogenic" effect) in a linear dose-dependent fashion. The fact that it had a bidirectional conditional effect on the diazepam cue drug demonstrates that a conditional response in drug --> drug conditioning cannot always be predicted on the basis of the behavioral response to the signaled drug. Consideration is given to possible reasons for these effects of diazepam --> yohimbine pairings in terms of the known neuropharmacological properties of yohimbine.

Animals↗
PubMed1977

Diazepam actions and plasma concentrations following ethanol ingestion.

In eight normal volunteers, the combination of ethanol (0.5 g/kg) and diazepam (10 mg) administered orally produced a greater decrease in motor performance on a pursuit rotor than diazepam alone. The pharmacologic effect of diazepam was enhanced by 73% and this potentiation was associated with significantly greater diazepam concentrations (p less than 0.01) than after diazepam alone. The failure to observe any increase in the concentrations of the principal metabolite, N-desmethyl diazepam, during the period of enhanced pharmacologic effect precludes any change in the demethylating metabolic process as being responsible. The data suggest (0.10 greater than p greater than 0.05) a trend to a smaller volume of distribution of diazepam when ethanol is administered prior to diazepam ingestion. The subjects showed acute tolerance to the effects of diazepam. Lower plasma concentrations on the ascending side of the plasma diazepam concentration versus time profile were linked with the same pharmacologic responses associated with a greater drug concentration on the descending portion, of the same curve.

Adolescent↗
PubMed1994

Preference for ethanol and diazepam in light and moderate social drinkers: a within-subjects study.

Preference for ethanol (versus placebo) and diazepam (versus placebo) was assessed in light and moderate social drinkers. The study was designed to investigate the relationship of habitual alcohol use to the subjective and behavioral effects of the two drugs. A secondary purpose of the study was to investigate relationships within subjects in their responses to ethanol and diazepam. Light drinkers (n = 13) who consumed one to five drinks per week and moderate drinkers (n = 14) who consumed seven or more drinks per week participated in two seven-session choice experiments, one assessing preference for 0.5 g/kg ethanol versus placebo and the other assessing preference for 20 mg diazepam versus placebo. Drugs were administered double-blind and double-dummy, and the order of participation in the two experiments was counterbalanced. Sessions were conducted during the evenings in a comfortable laboratory environment. The primary dependent measure was the number of times each subject chose the drug (i.e., ethanol or diazepam) over placebo. Subjective and objective measures of the drugs' effects were obtained using standardized self-report questionnaires and psychomotor tests. Whereas both groups preferred the ethanol over placebo (i.e., 63% and 83% ethanol choice for light and moderate drinkers, respectively), only the moderate drinkers preferred the diazepam over placebo (i.e., 40% and 73% diazepam choice for light and moderate drinkers, respectively). Subjective responses to the drugs were generally similar across the groups, although on some measures the light drinkers reported more marked drug effects. The number of times each subject chose ethanol was positively correlated with the number of times he or she chose diazepam (r = 0.57), and on subjective measures, responses to ethanol and diazepam were positively correlated. Thus, subjective and behavioral responses to diazepam and ethanol were related to habitual alcohol consumption, and most notably, moderate drinkers were more likely than light drinkers to prefer diazepam over a placebo.

Adult↗
PubMed1990

Effect of omeprazole and cimetidine on plasma diazepam levels.

The effects of steady state dosing with omeprazole and cimetidine on plasma diazepam levels have been studied in 12 healthy males. Single doses of diazepam (0.1 mg.kg-1 i.v.) were administered after one week of treatment with omeprazole 20 mg once daily, cimetidine 400 mg b.d. or placebo, and the treatment was continued for a further 5 days. Blood was collected for 120 h after the dose of diazepam for the measurement of diazepam and its major metabolite desmethyl diazepam. The mean clearance of diazepam was decreased by 27% and 38% and its half-life was increased by 36% and 39% after omeprazole and cimetidine, respectively. Neither drug had any apparent effect on the volume of distribution of diazepam. Desmethyldiazepam appeared more slowly after both omeprazole and cimetidine. It is concluded that the decrease in diazepam clearance was associated with inhibition of hepatic metabolism both by omeprazole and cimetidine. However, since diazepam has a wide therapeutic range, it is unlikely that concomitant treatment with therapeutically recommended doses of either omeprazole or cimetidine will result in a clinically significant interaction with diazepam.

Adult↗
PubMed2002

Diazepam potentiates the effects of endogenous catecholamines on contractility and cyclic AMP levels in rat ventricular myocardium.

Diazepam has phosphodiesterase (PDE) inhibitory activity and potentiates the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic agents. The present study was undertaken to determine whether diazepam enhances the contractile responses and cAMP levels induced by endogenous catecholamines in electrically driven rat right ventricular strips, and the effects are compared with that of the PDE inhibitor 3-isobutylmethylxantine (IBMX). Noradrenaline (10 nM(-1) microM), adrenaline (50 nM-500 microM) and tyramine (5-100 microM) produced concentration-dependent positive inotropic effects that were potentiated by the presence of 10 microM diazepam or IBMX. The diazepam-induced potentiation of the contractile effect of the sympathomimetic agents was not mimicked by 100 microM GABA nor was it antagonized by a 5 microM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. The beta(2)-adrenergic receptor agonist salbutamol (0.1-300 microM) also produced a concentration-dependent positive inotropic effect which was potentiated by the presence of 10 microM diazepam or 10 microM IBMX. However, the contractile effect of salbutamol, either alone or in the presence of diazepam or IBMX, was not affected by 50 nM ICI 118551, an antagonist of beta(2)-adrenergic receptors, but was virtually abolished by a 0.3 microM concentration of CGP 20712A, an antagonist of beta(1)-adrenergic receptors. Diazepam and IBMX also potentiated the increase in cAMP levels caused by these three sympathomimetic agents in this tissue. [(3)H]Noradrenaline release elicited by electrical stimulation or by tyramine was not affected by diazepam. The results demonstrate that diazepam, like the phosphodiesterase inhibitor IBMX, produces an inotropic and biochemical potentiation of the effects of endogenous catecholamines in rat myocardium. This effect is not due to the release of noradrenaline at the presynaptic level nor is it mediated by beta(2)-adrenergic receptors or benzodiazepine receptors of the central or peripheral type. The effect is probably consequential upon the phosphodiesterase inhibitory activity of diazepam.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Effects of diazepam on conditioned place preference induced by morphine or amphetamine in the rat.

RATIONALE: The drug-abuse literature suggests that benzodiazepines may be preferentially abused in conjunction with opioids rather than stimulants. OBJECTIVE: To investigate possible effects of diazepam on the reinforcing effects of morphine and amphetamine. METHODS: The effects of diazepam (0.5, 1 or 2 mg/kg) on the formation and expression of conditioned place preferences (CPP) induced by morphine sulphate (0.3, 0.8, 2 and 8 mg/kg) or D-amphetamine (0.4, 0.8, 2 or 2.5 mg/kg) were studied in an unbiased CPP paradigm. The action of diazepam (1 mg/kg) on conditioned and unconditioned locomotion induced by morphine (2 mg/kg) or amphetamine (2 mg/kg) was assessed. RESULTS: Rats that received conditioning injections of morphine in one environment displayed a preference for this environment. Pre-testing injections of diazepam did not alter the magnitude of this CPP. When diazepam was given with morphine during training, rats displayed a CPP for the environment paired with the two drugs. Injections of amphetamine in one environment also induced a preference for this environment. However, pre-testing injections of diazepam blocked the expression of amphetamine-induced CPP, and co-injections of diazepam blocked the formation of amphetamine CPP. Diazepam itself did not produce a CPP nor did it alter spontaneous place preferences. Diazepam equally blocked both morphine and amphetamine unconditioned and conditioned locomotor hyperactivity. This indicates that its effects on morphine and amphetamine CPP were not due to a differential effect on locomotion. CONCLUSIONS: Diazepam interferes with the reinforcing properties of amphetamines but not of morphine. The reinforcing effects of morphine and amphetamine are pharmacologically dissociable.

Amphetamine↗
PubMed1989

Local cerebral glucose utilization following subacute and chronic diazepam pretreatment: differential tolerance.

Local cerebral glucose utilization (LCGU) was determined in parallel groups of conscious rats receiving diazepam (0.3 mg/kg i.v.) either acutely or following subacute (5 mg/kg i.p. daily for 3 days) or chronic (5 mg/kg i.p. daily for 28 days) diazepam pretreatment, using 2-deoxyglucose quantitative autoradiography. Acute administration of diazepam reduced LCGU in 44 of the 66 structures examined compared to vehicle-treated controls. These included limbic, cortical and extrapyramidal structures, and areas associated with sensory processing. These data are consistent with many brain regions being functionally involved in the diverse acute pharmacological effects of diazepam and with the widespread distribution of benzodiazepine receptors throughout the neuroaxis. Following subacute treatment, when animals were tolerant to the sedative effects of diazepam, glucose use remained depressed in the majority of areas studied. However, in the locus coeruleus, dorsal tegmental nucleus and most structures associated with auditory processing, tolerance to the depressant effect of diazepam upon glucose use had occurred suggesting the importance of these structures in the sedative effect of diazepam. The most striking feature of the patterns of LCGU after chronic diazepam treatment was that tolerance had occurred in the mammillary body and subiculum. However, glucose use remained depressed in hippocampal layers and in structures that provide input to the hippocampus (e.g. raphe nuclei). These data suggest that the outflow of neuronal activity from the hippocampus to the mammillary body via the subiculum is restored after chronic treatment, and may implicate these pathways in the anxiolytic action of diazepam. Overall, it would appear that different neuroanatomical substrates underlie the various pharmacological effects of diazepam and that there may be regional differences in tolerance mechanisms.

Animals↗
PubMed1994

Inhibition of morphine tolerance and dependence by diazepam and its relation to the CNS Met-enkephalin levels.

The effect of diazepam on the development of morphine tolerance and dependence was investigated. Male Sprague-Dawley rats were rendered tolerant and dependent by subcutaneous implantation of six morphine pellets. Diazepam (0.025, 0.25 or 2.5 mg/kg body weight) was once daily injected intraperitoneally into rats starting on the first day of implantation. Antinociception was measured by tail-flick (TF) and hot plate (HP) tests, and the extent of sedation determined by a rotarod test before and one hour after diazepam injections everyday for 5 days. Physical dependence on morphine was assessed by an antagonist-precipitated abstinence syndrome on the fifth day of treatment by injecting naloxone 10 mg/kg subcutaneously. Diazepam (0.025-2.5 mg/kg body weight) did not produce significant antinociception or sedation (sensorimotor impairment) in rats implanted with placebo pellets. Diazepam (0.25 and 2.5 mg/kg) inhibited tolerance to TF antinociception in rats implanted with morphine pellets. Sedation as evidenced by sensorimotor impairment induced by morphine pellet implantation was not influenced by diazepam (0.025-2.5 mg/kg). Diazepam administration (0.25 mg/kg) also decreased the degree of jumping behavior observed following naloxone injection in morphine pellet implanted rats. Serum morphine concentration in morphine-diazepam treated rats was not significantly different from that in morphine-saline treated rats. Finally, a decrease in the Met-enkephalin levels observed in the hypothalamus, hippocampus, cortex and spinal cord of morphine dependent rats was reversed by injecting diazepam along with morphine pellet implantation. These results suggest that diazepam inhibits morphine tolerance and dependence, and also prevents morphine-induced decrease in the CNS Met-enkephalin levels in morphine dependent rats.

Animals↗
PubMed1995

Interethnic difference in omeprazole's inhibition of diazepam metabolism.

OBJECTIVES: To compare the effect of omeprazole, a substrate and inhibitor of CYP2C19, on diazepam metabolism in white and Chinese subjects. SUBJECTS AND METHODS: The study, which took place at a clinical research center in a University Hospital, was designed as a double blind, crossover, two-stage study; each stage lasted 21 days and was separated by 4 weeks. Subjects were eight white and seven Chinese men who were extensive metabolizers of debrisoquin and mephenytoin. The subjects received, in a randomized order, omeprazole, 40 mg/day, and placebo for 21 days, followed by a 10 mg oral dose of diazepam. Diazepam and desmethyldiazepam plasma concentrations were determined by HPLC during a 26-day period after diazepam administration. RESULTS: In white subjects omeprazole treatment decreased diazepam clearance by 38% +/- 4.4% and increased desmethyldiazepam area under the plasma concentration-time curve (AUC) by 42.4% +/- 7.0%. In contrast, diazepam oral clearance decreased by only 20.7% +/- 7.3% and desmethyldiazepam AUC decreased by 25.4% +/- 4.6% in the Chinese group. The decrease in diazepam clearance and the prolongation in diazepam and desmethyldiazepam elimination half-lives after administration of omeprazole were significantly greater in the white group than in the Chinese group (p < 0.03, p < 0.001, and p < 0.004, respectively). In the absence of omeprazole, diazepam oral clearance was marginally greater (mean +/- SEM) (34.4 +/- 2.8 ml/min versus 25.2 +/- 3.5 ml/min, p = 0.057, respectively) and the AUC of desmethyldiazepam was significantly lower (8794 +/- 538 micrograms/L.hr versus 16,358 +/- 2985 mg/L.hr, p = 0.04, respectively) in the white subjects compared with the Chinese subjects. CONCLUSION: The extent of the inhibitory effect of omeprazole on diazepam metabolism is dependent on ethnicity. Further studies are needed to determine the mechanism responsible for this phenomenon.

Adult↗
PubMed1996

Tolerance to the ataxic effects of diazepam in guinea pig is not associated with a reduced sensitivity of GABAA receptors in the vestibular nucleus.

Some studies have suggested that drug tolerance observed following repeated benzodiazepine exposure may be associated with the development of a subsensitivity to gamma-aminobutyric acid (GABA) in dorsal raphe and hippocampal neurons. In other areas such as the substantia nigra such subsensitivity has not been found. The aim of the present study was to determine whether tolerance develops to the ataxic effects of diazepam on the righting reflex following low (i.e. 2 mg/kg i.p.), multiple daily doses and, if so, whether it is correlated with the development of a subsensitivity of medial vestibular nucleus neurons to the selective GABAA receptor agonist, isoguvacine. Guinea pigs which received i.p. vehicle injections three times daily for 5 days, or single daily doses of 2 or 6 mg/kg diazepam, showed increased righting reflex latencies in response to a 6 mg/kg diazepam challenge dose. However, guinea pigs which received 2 mg/kg diazepam i.p., three times daily for 5 days, exhibited minimal or no ataxia when given the same diazepam challenge dose, indicating the development of tolerance. Brain stem slices including the medial vestibular nucleus were removed from guinea pigs which had received the same diazepam and vehicle three times daily injection schedules, and recordings were made from single neurons during superfusion of isoguvacine. Although medial vestibular nucleus neurons from animals which received chronic diazepam administration showed smaller decreases in firing rate in response to 10(-8) M isoguvacine, the difference was not statistically significant compared to neurons from animals which received vehicle treatment or acute diazepam treatment. Resting activity was also similar between the diazepam and vehicle groups, in contrast to a previous study which had shown hyperexcitability in medial vestibular nucleus cells from animals which had received single daily injections for up to 60 days. These results suggest that, in contrast to studies which have employed single daily doses, tolerance to the ataxic effects of diazepam on the righting reflex occurs rapidly with divided daily doses. However, this tolerance is not correlated with significant changes in the sensitivity of GABAA receptors on medial vestibular nucleus neurons.

Animals↗
PubMed1986

Effects of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 on amygdaloid kindled seizures and the anticonvulsant efficacy of diazepam.

The anticonvulsant effectiveness of the benzodiazepine antagonists RO 15-1788, CGS-8216 and PK-11195 were evaluated against threshold and suprathreshold (400 microA) stimulation in fully amygdaloid-kindled rats. Pretreatment with either RO 15-1788 (3, 10 and 30 mg/kg), CGS-8216 (3, 10 and 30 mg/kg) or PK-11195 (10 and 60 mg/kg) failed in this study to modify consistently either the afterdischarge thresholds or elicited suprathreshold seizures or duration of afterdischarge. Using a double injection paradigm, the effectiveness of these three benzodiazepine antagonists to reverse the anti-convulsant and behavioral effects of diazepam were studied. When diazepam (3 mg/kg) was injected 15 min before or after a second injection of the vehicle control DMSO (0.25 ml/kg), a significant reduction in the duration of afterdischarge and seizure rank, elicited by a suprathreshold stimulation in amygdaloid-kindled rats, occurred. When either CGS 8216 (10 mg/kg) or RO 15-1788 (10 mg/kg) were given 15 min before diazepam (3 mg/kg) prior to stimulation, the anticonvulsant properties of diazepam were blocked. When RO 15-1788 (10 mg/kg) was given 15 min after diazepam, antagonism of the anticonvulsant effects on diazepam was shown. However, when either CGS-8216 (10 mg/kg) or PK-11195 (10 and 60 mg/kg) were given 15 min after diazepam (3 mg/kg), the anticonvulsant properties of diazepam were not blocked. The anticonvulsant effects of diazepam were reversed when CGS-8216 (10 mg/kg) was given 5 min after diazepam (3 mg/kg) or when a larger dose (30 mg/kg) was given at the same 15 min interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed1986

The effect of diazepam upon local cerebral glucose use in the conscious rat.

The effects of diazepam (0.1-1.0 mg/kg i.v.) upon local cerebral glucose utilization, were analysed in 61 anatomically discrete areas of the conscious rat brain using [14C]-2-deoxyglucose quantitative autoradiography. The administration of diazepam resulted in significant reductions in the rate of glucose use in every region investigated. The regional pattern of alterations in glucose utilization was rather homogeneous, with the majority of brain regions analysed showing reductions of between 20 and 40% in response to 0.3 mg/kg diazepam. Only two regions of the central nervous system differed significantly from the widespread, homogeneous reductions. In the mammillary body, the rate of glucose utilization was more sensitive to depression than elsewhere in the brain (55% reductions following 0.3 mg/kg diazepam), whilst in the lateral amygdala, the rate of glucose use was less sensitive (8% reductions following 0.3 mg/kg diazepam). The effects of diazepam were compared to those elicited by i.v. injection of the gamma-aminobutyric acid (GABA) agonists, muscimol and tetrahydroisoxazolopyridinol (THIP), as reported previously by the authors. Although muscimol and THIP, like diazepam, reduced glucose use in every region of the brain, visual inspection of the autoradiograms suggested that whilst the patterns of regional responsiveness to the two GABA agonists were almost identical, they were different to the pattern of response evoked by diazepam. A rigorous system of analysis was devised making use of the dose-response profiles in each of the 61 brain areas to construct a regional hierarchy of responsiveness to the three drugs and allowing comparison of their effects on the brain as a whole. This critical form of data evaluation revealed that there was a more regionally homogeneous response to diazepam than to either muscimol or THIP, and whilst the regional hierarchy of responses to the GABA agonists was very similar, both differed from diazepam. It would appear that whilst benzodiazepines may interact with the GABA receptor, their effects upon the integrated functional activity of the brain as a whole differs markedly from that evoked by putative GABA receptor agonists.

Animals↗