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PubMed2006

Drugs, sweat, and fears: a comparison of the effects of diazepam and methylphenidate on fear conditioning.

RATIONALE: Classical conditioning of a fear response involves the formation of an association between a stimulus and an emotional response and can be seen as a basic form of emotional memory. While both benzodiazepines and stimulant drugs may influence the formation of episodic memories for emotional events, their effects on fear conditioning are less clear. OBJECTIVES: This study compared the effects of diazepam with methylphenidate on fear conditioning. MATERIALS AND METHODS: In a single-session between groups design with three conditions [placebo, diazepam (10 mg), and methylphenidate (40 mg)], classical conditioning of a skin conductance response to a visual stimulus previously paired with a 100-db white noise was tested in 45 healthy volunteers. RESULTS: Diazepam blocked fear conditioning, despite responses to the unconditioned aversive stimulus and neutral control stimulus being unimpaired. Conditioning remained intact after methylphenidate. Conditioned responses were not extinguished completely by the end of the experiment, and it was not possible to draw conclusions about the effects of the drugs on extinction. CONCLUSIONS: Although diazepam has well-documented amnesic effects, it has not been found to affect implicit forms of memory like perceptual and conceptual priming. As the present study found impaired fear conditioning after diazepam, it adds weight to recent findings that emotional memories are disproportionately impaired by the benzodiazepines.

Adult↗

PubMed2000

Differences in anxiety-related behaviours and in sensitivity to diazepam in inbred and outbred strains of mice.

RATIONALE: Natural strain differences exist in mice for behavioural traits such as emotional reactivity. OBJECTIVE: The present experiments compared the behavioural profiles of nine strains of mice (BALB/c, C57BL/6, C3H, CBA, DBA/2, NMRI, NZB, SJL, Swiss) in two models of anxiety after the administration of the benzodiazepine diazepam. METHODS: The tests used were the light/dark choice task and the elevated plus-maze, two well-validated anxiolytic screening tests. RESULTS: In vehicle-treated animals, differences on variables designed to measure anxiety-related behaviours were observed in both tests. In the light/dark test, the strains could be divided into three distinct groups: two non-reactive strains (NZB and SJL), an intermediate-reactive group (C3H, CBA, DBA/2, NMRI, C57BL/6 and Swiss), and one highly reactive strain (BALB/c). In the elevated plus-maze, SJL, NMRI, CBA and, to a lesser extent, C3H strains of mice, consistently showed low levels of anxiety-related behaviours. Intermediate levels were seen in the Swiss and BALB/c strains, and high levels of emotional reactivity were seen in C57BL/6, DBA/2 and NZB. The strain distribution between the light/dark and the elevated plus-maze tests shows similarities and differences, suggesting that each of these experimental procedures represents a different set of behaviours. Marked differences between a number of strains of mice in their sensitivity to the anxiolytic-like action of diazepam were observed in both the light/dark and the elevated plus-maze tests. Mice of the BALB/c, Swiss and, to a lesser extent, CBA and C3H strains were responsive to diazepam in both tests, although in the case of CBA mice, effects may have been contaminated by behavioural suppression. SJL mice were largely unresponsive to the action of the benzodiazepine in both tests, whereas in C57, DBA/2, NMRI and NZB mice, diazepam produced positive effects only in the elevated plus-maze. CONCLUSION: The finding of differential strain distributions both with and without diazepam treatment in the light/dark and the elevated plus-maze tests, indicates that not all strains of mice are suitable for investigating the effects of GABA/BZ receptor ligands. This study may thus provide a useful guide for choosing the best strain of mice for studying the pharmacology of fear-related behaviours.

Animals↗

PubMed1996

Possible inhibitory effect of diazepam on the metabolism of zotepine, an antipsychotic drug.

Effects of smoking and cytochrome P450 2C19 (CYP2C19) status on the single dose kinetics of zotepine and pharmacokinetic interaction between zotepine and diazepam were investigated. In 14 healthy volunteers, the pharmacokinetics of zotepine after a single oral 25 mg dose were compared between eight smokers and six non-smokers, or between seven extensive metabolizers (EMs) and seven poor metabolizers (PMs) of S-mephenytoin. There was no significant difference in any pharmacokinetic parameters between smokers and non-smokers, or between the EM and PM groups. In 17 patients treated with zotepine 80-340 mg/day, intra-individual changes in plasma concentrations of zotepine caused by coadministration of diazepam 10 mg/day for 2 weeks were examined. Plasma concentrations of zotepine were significantly increased after coadministration of diazepam (P < 0.05). Consequently, it is suggested that neither smoking nor CYP2C19 status affects the metabolism of zotepine. The elevation in plasma concentrations of zotepine after coadministration of diazepam may be a result of competitive inhibition of zotepine metabolism by diazepam via other isoenzyme than CYP2C19, e.g., CYP3A4.

Adult↗

PubMed1997

Enhancement by flumazenil of dopamine release in the nucleus accumbens of rats repeatedly exposed to diazepam or imidazenil.

The effect of long-term treatment (three times daily for 3 weeks) with a behaviorally relevant dose of the benzodiazepine receptor partial agonist imidazenil (0.5 mg/kg, IP) on basal dopamine release in the nucleus accumbens of freely moving rats was compared with that of diazepam (3 mg/kg, IP), a benzodiazepine receptor full agonist. Challenge doses of imidazenil and diazepam decreased the extracellular dopamine concentration in the nucleus accumbens by approximately the same extent in animals repeatedly exposed to vehicle or to the respective drug. Moreover, the abrupt discontinuation of long-term treatment with diazepam or imidazenil failed to affect basal dopamine release in this brain area during the first 5 days of withdrawal. In contrast, administration of the benzodiazepine receptor antagonist flumazenil (4 mg/kg, IP) elicited a marked increase (95 or 60%) in dopamine release in the nucleus accumbens 6 h after withdrawal of diazepam or imidazenil, respectively. Flumazenil induced a similar but smaller effect (50% increase) 5 days after diazepam withdrawal but had no effect 5 days after discontinuation of imidazenil treatment. The results support an involvement of the mesoaccumbens dopaminergic neurons in the withdrawal syndrome precipitated by flumazenil and allow further differentiation of benzodiazepine receptor partial and full agonists with respect to dependence liability of dopaminergic neurons in the nucleus accumbens.

Animals↗

PubMed1998

Sensitivity of the fear-inhibited light reflex to diazepam.

We have shown previously that pupil diameter increases and the amplitude of the pupillary light reflex is reduced when subjects are under threat of an aversive event (electric shock), and that light reflex amplitude correlates negatively with subjective anxiety. We have suggested that the "fear-inhibited light reflex" paradigm could be used as a laboratory model of human anxiety. In the present study, we examined whether two doses (5 mg and 10 mg) of the anxiolytic drug diazepam would antagonize the effects of threat on the pupillary light reflex. Twelve healthy male volunteers participated in three weekly sessions, each associated with one of three treatments (diazepam 5 mg or 10 mg or placebo) in a double-blind, balanced, cross-over design. The light reflex was recorded during either the anticipation of a shock ("threat" blocks) or periods in which no shocks were anticipated ("safe" blocks). At the end of each "threat" or "safe" block, subjects rated their anxiety using visual analogue scales. Two-factor ANOVA (treatment x condition) showed that diazepam treatment antagonized the effect of threat on light reflex amplitude in a dose-dependent manner but it did not affect the threat-induced increase in pupil diameter. Diazepam had no effect on the pupillary light reflex in the "safe" condition. Diazepam also reduced subjective anxiety and alertness in the threat condition. These results show the sensitivity of the threat-induced reduction of light reflex amplitude to anxiolytic drugs, and provide further evidence for the utility of the fear-inhibited light reflex paradigm as a laboratory model of human anxiety.

Adolescent↗

PubMed1998

Dual task performance after diazepam intake: can resource depletion explain the benzodiazepine-induced amnesia?

It was tested whether a depletion in resources can account for the benzodiazepine-induced memory impairment. In two experiments, it was examined whether dividing attention had a disproportionately detrimental effect on learning semantically related and unrelated word pairs after diazepam intake. Word pairs had to be learned in both a single task condition and while performing a visual discrimination task concurrently (dual task condition). Moreover, the complexity of the visual discrimination task was manipulated systematically. Diazepam (15 mg, orally) or placebo was administered in a double-blind, between-subjects design. Subjects after diazepam intake were clearly impaired in learning unrelated word pairs, but not in learning related word pairs. Dividing attention in the dual task condition was associated with a reduction in learning unrelated word pairs, but this was not disproportionately reduced after diazepam intake. Moreover, the magnitude of resource depletion did not correlate with the severity of the diazepam-induced memory impairment. In general, the pattern of results does not support the hypothesis that a depletion of resources can explain the benzodiazepine-induced memory impairment.

Adult↗

PubMed2001

Severe and prolonged sedation in five neonates due to persistence of active diazepam metabolites.

UNLABELLED: Five neonates who suffered from an unexpected long period of respiratory failure, muscular hypotonia, and drowsiness were observed in a retrospective study. Prior to this general depression, unusually high doses of diazepam were administered to all patients via intravenous bolus injection. Serum levels of diazepam and its active metabolites were substantially elevated in the course of the disease. The persistence of the very long-acting N-desmethyldiazepam with considerable extension in neonates and even more exaggerated in premature infants is emphasized due to the reduced capacity of the hepatic biotransformation system. CONCLUSION: The intravenous application of diazepam imposes a risk of marked and prolonged general depression in neonates. Pronounced adverse effects are to be expected for prematures even after a single diazepam intravenous bolus if the dosage is not appropriate. Diazepam should not be used for short sedation and is not the drug of choice for anticonvulsant therapy in neonates.

Biotransformation↗

PubMed2002

Effect of oral diazepam on anal continence after low anterior resection: a preliminary study.

The aim of the present study was to investigate the effect of oral diazepam on anal incontinence after low anterior resection for rectal cancer. Five patients with persistent incontinence after low anterior resection for rectal cancer (median level of anastomosis was 4.0 cm from the anal verge) were treated with oral diazepam (2 mg/day) 9-90 months after surgery. Grade and frequency of anal incontinence, the need for a protective pad and changes of lifestyle were recorded to the Cleveland Clinic's continence grading scale; anorectal manometry was performed before and after 3 months of treatment. All patients improved on treatment although occasional minor soiling persisted in two patients. Continence score improved from 14 (median, range 9-16) to 0 (range 0-12) after taking diazepam. Improvement occurred within a week after administration of diazepam. Although the patients improved symptomatically, anorectal manometry failed to demonstrate any significant changes. In conclusion, oral administration of diazepam may be worthwhile in the attempt to improve anal continence after low anterior resection.

Aged↗

PubMed1990

Growth hormone response to intravenous diazepam and placebo in 82 healthy men.

Growth hormone (GH) response to placebo and two different doses of diazepam (0.12 mg/kg and 0.20 mg/kg) were evaluated in 82 healthy young men. Both diazepam doses had a significant effect on the growth hormone secretion, with peak values occurring between 30 and 60 min postinfusion, after which levels returned to baseline. There was also a small but significant change in this hormone over time after placebo, but this was reflected by a slow rise following the saline infusion. Individual GH responses to diazepam were variable and, when a cut-off point of 7.5 ng/ml GH increase before 90 min postdrug administration was used, 1% of the men demonstrated a response after placebo, 17% after low-dose diazepam, and 37% following high-dose diazepam. The clinical implications and limitations of these findings are discussed.

Adolescent↗

PubMed1984

Dissociation of limbic structures by pharmacological effects of diazepam on electrical self-stimulation in the mouse.

The effect of diazepam was tested on self-stimulation (SS) in 21 mice implanted with a bipolar electrode in the lateral hypothalamus (LH), the dorsolateral hippocampus (HPC) or the lateral entorhinal cortex (LEC). Diazepam, injected i.p. in doses of 0.5, 1 and 2 mg/kg, significantly increased SS rates with electrodes in LH while 4 and 8 mg/kg of diazepam had no significant effect. At low doses, similar increases were seen in mice with LEC electrodes but high doses produced a significant suppression. HPC animals showed an almost total suppression of SS beginning at 2 mg/kg of diazepam; lower doses had no significant effect. The results indicate that entorhinal and hippocampal SS are at least partly independent phenomena; in addition, the suppression of SS by moderate doses of diazepam remains specific to the HPC among the brain structures studied to date.

Animals↗

PubMed1987

Benzodiazepine antagonist Ro 15-1788 (flumazepil) attenuates the anticonvulsant activity of diazepam in epileptic fowl.

The ability of the imidazobenzodiazepine Ro 15-1788 to displace diazepam from brain membranes in vitro and to antagonize the anticonvulsant activity of diazepam in vivo was determined in epileptic fowl. At doses of 1.0 mg/kg and higher, Ro 15-1788 significantly attenuated the anticonvulsant action of diazepam (1.0 mg/kg) in epileptic chickens. Ro 15-1788 alone exerted no anticonvulsant activity even in doses as high as 10 mg/kg. Specific binding of 10 nM [3H]diazepam to whole homogenate fractions prepared from cerebral hemispheres of epileptic fowl was inhibited by Ro 15-1788 with an IC50 of 8.5 nM and the Ki was determined to be 4.25 nM. These results suggest that Ro 15-1788 competes directly with diazepam for a binding site involved in producing anticonvulsant activity.

Animals↗

PubMed1987

The effect of diazepam on hippocampal EEG in relation to behavior.

Male mice of the BALB/cByJ and C57BL/6 strains were implanted with electrodes in the CA1 area of the hippocampus to record rhythmic slow-wave activity (RSA) or 'theta' EEG activity. The EEG spectral characteristics and the animal's motor behavior were studied while the animals walked on a moving belt (2.2 cm/s) both before and after i.p. injections of diazepam (Valium, 2 mg/kg) or vehicle. EEG spectral analyses were carried out on-line by computer. Diazepam produced a dissociation of locomotion and RSA. (1) Uninjected and vehicle-injected mice showed typical RSA (7-8 Hz) while walking. (2) Under diazepam, 7-8 Hz RSA virtually disappeared and was replaced in the temporally averaged records by RSA with a sharp, narrow-band peak at 4-5 Hz. (3) This lower-frequency RSA was associated with immobility if, and only if, the immobility immediately followed walking. This was true whether the animal itself stopped walking or the experimenter stopped the moving belt. This theta activity predominated for about 30 s and had disappeared after 2 min. Locomotion, on the other hand, was accompanied by irregular EEG activity. (4) Scopolamine (i.p. 1 mg/kg), a cholinergic blocker, greatly reduced the diazepam-induced 4-5 Hz RSA, but also partially restored 7-8 Hz RSA. The possibility that the effects of diazepam on hippocampal EEG involve changes in septohippocampal cholinergic activity is discussed.

Animals↗

PubMed1988

Diazepam attenuation of somatostatin-induced motor disturbances and neurotoxicity.

Intracerebroventricular somatostatin administration to conscious rats results in a characteristic motor abnormality (barrel rotation), convulsions that are frequently fatal and destruction of cerebellar Purkinje cells. This study demonstrates that each of these manifestations of this neuropeptide can be attenuated by pretreatment with diazepam (Valium, 5 mg/kg, i.p.) but not in vehicle-pretreated controls. Specifically, the incidence of mortality was reduced from 5/12 controls to 2/20 diazepam-treated rats, the incidence of barrel rotation was reduced from 6/12 controls to 2/20 diazepam-treated rats and the incidence of Purkinje cell death was reduced from 4/4 examined controls to 4/13 diazepam-treated animals. Vehicle pretreated rats did not differ from untreated rats. Thus, in addition to blocking somatostatin-induced motor dysfunction and mortality, diazepam offers significant protection from central neuronal cell death in the cerebellar cortex.

Animals↗

PubMed1989

Co-administration of Ro 15-1788 prevents diazepam-induced retardation of recovery of function.

Following unilateral lesions of the anteromedial cortex, recovery from somatosensory asymmetry reliably occurs within about 10 days. Chronic exposure to diazepam significantly delays this recovery. In the present study, co-administration of Ro 15-1788, a benzodiazepine antagonist (i.e. it blocks the negative and positive allosteric modulation of GABA), prevented diazepam-induced retardation of recovery from somatosensory asymmetry. Nocturnal ambulatory (motor) activity was not different between rats receiving diazepam-alone and those receiving Ro 15-1788 in combination with diazepam. These data suggest that the benzodiazepine receptor is importantly involved in the detrimental effects of diazepam on recovery, and that non-specific behavior sedation plays little or no role.

Animals↗

PubMed1991

Muscimol-associated changes in local cerebral glucose use following chronic diazepam administration.

Local cerebral glucose use (LCGU) was determined in parallel groups of conscious rats receiving muscimol (1.5 mg/kg i.v.) after either saline pretreatment (28 days i.p.), saline pretreatment (27 days i.p.) followed by a single dose of diazepam (5 mg/kg i.p.) 24 h prior to muscimol administration, or chronic diazepam pretreatment (5 mg/kg i.p. daily for 28 days). Acute administration of muscimol produced a significant reduction in LCGU in 25 out of 66 structures examined compared with vehicle-treated controls. The pattern of reductions was heterogeneous. Thalamic and most cortical areas showed reductions of the order of 30-45%, whereas more modest depressions of 15-20% were observed in some limbic structures (e.g. basolateral amygdala, anterior thalamic nuclei, nucleus accumbens, subiculum). This contrasts with the more extensive and homogeneous pattern of LGCU reductions (around 20%) produced by diazepam. Neither acute diazepam treatment the previous day nor chronic diazepam pretreatment altered the LGCU response to muscimol. These data suggest that high-affinity GABA receptor-mediated responses are unchanged by both acute and chronic benzodiazepine pretreatment. It would appear unlikely that alterations in these responses contribute to the mechanism of benzodiazepine tolerance.

Animals↗

PubMed1994

Perinatal administration of diazepam alters sexual dimorphism in the rat accessory olfactory bulb.

The present study examines the effects of pre and/or early postnatal administration of diazepam on the mitral cell and on the light and dark granule cell populations in the sexually dimorphic accessory olfactory bulb of the rat. Quantitative differences related to sex were observed in the numbers of the three types of neurons, with vehicle males showing greater numbers of cells than vehicle females. The number of mitral cells in males decreased to the levels shown by female rats following prenatal and pre-postnatal diazepam treatments, whereas the DZ treatments did not affect the females. In addition, the diazepam administration during the prenatal, postnatal and pre-postnatal periods decreased the numbers of both light and dark granule cells in males, while these two granule cell subpopulations were not affected in diazepam treated females. These results indicate that perinatal administration of diazepam can alter the sexual dimorphism in the accessory olfactory bulb and that the GABAA/benzodiazepine receptor complex is involved in the sexual differentiation this part of the brain.

Animals↗

PubMed1994

Diazepam attenuates hyperexcitability and mechanical hypersensitivity of dorsal horn convergent neurones during reperfusion of the rat's tail following ischaemia.

We have investigated the involvement of the GABAA-benzodiazepine receptor complex in nociceptive activity of convergent neurones in the spinal cord during ischaemia and reperfusion of their receptive fields on the rat's tail. In enflurane anaesthetized rats, extracellular recordings were made from convergent neurones located throughout the dorsal horn before, during and after 30 min of ischaemia. Following intrathecal saline pretreatment, there was a significant increase in spontaneous firing rate during ischaemia (219 +/- 21%, P < 0.02, n = 10) which persisted during reperfusion. After 10 min of reperfusion, the neurones exhibited a greater response than before ischaemia to both innocuous brush (54 +/- 11%, P < 0.05, n = 10) and noxious pinch (72 +/- 14%, P < 0.02, n = 10) and the enhanced sensitivity persisted over the 60-min reperfusion period. During reperfusion, receptive field size increased in most neurones tested. Intrathecal diazepam (100 and 500 micrograms) abolished the hyperexcitability and the hypersensitivity to both innocuous and noxious mechanical stimulation during reperfusion. The highest dose of diazepam (500 micrograms) also attenuated the increase in spontaneous firing rate during ischaemia. Diazepam, at the doses tested, had no effect on receptive field enlargements during reperfusion. The effect of 100 micrograms of diazepam was partially reversed by flumazenil (1 mg/kg i.p.) but not by naloxone (1 mg/kg i.p.). In the absence of ischaemia, diazepam had no effect on spontaneous firing rate nor on the responses to innocuous or noxious mechanical stimulation. Our results support an antinociceptive role for benzodiazepines in the dorsal horn elements responsible for reperfusion hyperalgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Correlations between EEG changes induced by diazepam and the localization of epileptic spikes and seizures.

We evaluated the EEG reaction to an intravenous injection of diazepam as an additional tool in difficult localization problems in epilepsy. The normal reaction to diazepam being an increase in beta activity, it was assumed that a poor increase indicated an abnormal region. This method was tested in 21 epileptic patients having chronically implanted intracerebral electrodes. Beta activity before and after injection was quantified by spectral analysis; increases were compared in homologous contralateral channels. In 12 of the 21 cases the area of poorest response to diazepam was identical to that of seizure onset. In 7 cases, there was some overlap between the area of poorest diazepam response and that of seizure onset, but they did not exactly coincide. In two cases there was no overlap between the two areas. Agreement was slightly higher when comparing diazepam response and area of highest interictal spike activity. This procedure is simple and without risk, particularly compared to the thiopental injection which is used for the same purpose. It is helpful in determining abnormal areas when localization information from various diagnostic sources are conflicting. Even when the epileptic focus is well defined, it can point to other poorly functioning areas.

Adult↗