Simultaneous determination of diazepam and its active metabolites in rat serum, brain and cerebrospinal fluid by high-performance liquid chromatography

Klockowski, Patricia M.; Levy, Gerhard

doi:10.1016/0378-4347(87)80472-3

Cited by 18 publications

(9 citation statements)

References 10 publications

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“…On the basis of the literature, we can estimate that DZ at the dose of 5 mg/kg will be quickly metabolized to its active metabolites N-desmethyldiazepam and oxazepam in mice, and that hardly any DZ should be present in the brain after 2 h (Coutinho et al, 1969;Greenblatt and Sethy, 1990). N-desmethyldiazepam, which has roughly the same affinity to BZ receptors and the same hypnotic potency as DZ (but less anticonvulsant potency than diazepam) (Frey and Löscher, 1982;Gobbi et al, 1987;Klockowski and Levy, 1987), disappears from the brain at around 12 h, whereas oxazepam has the longest elimination half-life of the active DZ metabolites and might be detectable at a very low level still at 24 h but unlikely to be detected at 48 h (Greenblatt and Sethy, 1990). However, oxazepam has clearly less hypnotic and anticonvulsant efficacy than DZ (Frey and Löscher, 1982;Klockowski and Levy, 1987).…”

Section: Discussionmentioning

confidence: 99%

“…N-desmethyldiazepam, which has roughly the same affinity to BZ receptors and the same hypnotic potency as DZ (but less anticonvulsant potency than diazepam) (Frey and Löscher, 1982;Gobbi et al, 1987;Klockowski and Levy, 1987), disappears from the brain at around 12 h, whereas oxazepam has the longest elimination half-life of the active DZ metabolites and might be detectable at a very low level still at 24 h but unlikely to be detected at 48 h (Greenblatt and Sethy, 1990). However, oxazepam has clearly less hypnotic and anticonvulsant efficacy than DZ (Frey and Löscher, 1982;Klockowski and Levy, 1987). Thus, it is unlikely that the possible residual oxazepam is directly involved in the glutamate receptor modification 24-72 h after a single injection of DZ.…”

Section: Discussionmentioning

confidence: 99%

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Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons after a Single Dose of Benzodiazepine Agonists

Heikkinen

Möykkynen

Korpi

2008

Neuropsychopharmacol

103

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Initial effects of drugs of abuse seem to converge on the mesolimbic dopamine pathway originating from the ventral tegmental area (VTA). Even after a single dose, many drugs of abuse are able to modulate the glutamatergic transmission activating the VTA dopamine neurons, which may represent a critical early stage in the development of addiction. Ligands acting on the benzodiazepine site of the inhibitory g-aminobutyric acid type A (GABA A ) receptors are known to be rewarding in animal models and have abuse liability in humans, but notably little evidence exists on the involvement of the mesolimbic dopamine system in their effects. Here we report that single in vivo doses of benzodiazepine-site agonists, similar to morphine and ethanol, induce a modulation in the glutamatergic transmission of VTA dopamine neurons. This is seen 24 h later as an increase in the ratio between a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory currents using whole-cell patch-clamp configuration in mouse VTA slices. The effect was due to increased frequency of spontaneous miniature AMPA receptor-mediated currents. It lasted at least 3 days after the injection of diazepam, and was prevented by coadministration of the benzodiazepine-site antagonist flumazenil or the NMDA receptor antagonist dizocilpine. A single injection of the GABA A receptor a1 subunit-preferring benzodiazepine-site ligand zolpidem also produced an increase in the AMPA/NMDA ratio in VTA dopamine neurons. These findings suggest a role for the mesolimbic dopamine system in the initial actions of and on neuronal adaptation to benzodiazepines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons after a Single Dose of Benzodiazepine Agonists

Heikkinen

Möykkynen

Korpi

2008

Neuropsychopharmacol

103

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“…The procedure was adapted from the method reported by Klockowski and Levy (1987). For the unknown samples, the whole brain was removed, weighed, placed in an ice-cold tube containing 2.5 mg medazepam (internal standard) and 1.5 mL borate buffer (pH 9).…”

Section: Determination Of Diazepam and Its Active Metabolites (Desmetmentioning

confidence: 99%

Relationship between cerebral pharmacokinetics and anxiolytic activity of diazepam and its active metabolites after a single intra‐peritoneal administration of diazepam in mice

Dailly¹,

Hascoët²,

Colombel³

et al. 2002

Human Psychopharmacology

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The relationship between the cerebral pharmacokinetics of diazepam and its active metabolites (desmethyldiazepam, oxazepam) and the anxiolytic effect evaluated by the four-plates test and the light/dark test were investigated after a single intra-peritoneal injection of diazepam (1 mg/kg or 1.5 mg/kg). For up to 30 min after administration, the sedative effect interfered with the anxiolytic effect, thus the results of the anxiolytic effect were not interpretable. From 30 min to 60 min after administration, this interference disappeared, the cerebral level of benzodiazepines was stable (the brain elimination of diazepam was compensated for by the appearance of desmethyldiazepam followed by oxazepam) but the anxiolytic effect decreased dramatically in all the tests with diazepam 1 mg/kg or 1.5 mg/kg. The acute tolerance to benzodiazepines and the difference of affinity for subtypes of GABA(A) receptors between diazepam, desmethyldiazepam, oxazepam could explain this result.

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“…In the past, the CSF of rats was assayed infrequently for neurogenic molecules because of the difficulty of collection and low sample volume yields. However, with the advent of more sensitive assay techniques such as enzyme-linked immunosorbent assay and high-performance liquid chromatography (Klockowski and Levy, 1987), the low CSF yield from rats is no longer a limitation in utilization for biomarker measurement in a variety of toxicities and neurological disorders. Numerous techniques have been described for CSF collection in rats permanently implanted with cannulae or by guided cannulae (Curzon et al, 1985;De La Riva and Yeo, 1985;Jolkkonen et al, 1986;Sanvitto et al, 1987;Dingemanse et al, 1988;Sokomba et al, 1988;Takemoto, 1991;Westergren and Johansson, 1991;Halonen et al, 1992;Consiglio and Lucion, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…Numerous techniques have been described for CSF collection in rats permanently implanted with cannulae or by guided cannulae (Curzon et al, 1985;De La Riva and Yeo, 1985;Jolkkonen et al, 1986;Sanvitto et al, 1987;Dingemanse et al, 1988;Sokomba et al, 1988;Takemoto, 1991;Westergren and Johansson, 1991;Halonen et al, 1992;Consiglio and Lucion, 2000). Ylitalo et al (1976) and Klockowski and Levy (1987) described the collection of CSF from the cisterna magna of anesthetized rats via percutaneous puncture. CSF from rats is routinely analyzed in many pharmaco-toxicologic (Curzon et al, 1985;De La Riva and Yeo, 1985;Jolkkonen et al, 1986;Kornhuber et al, 1986b;Takemoto, 1991) and biochemistry (Ylitalo et al, 1976;Westergren and Johansson, 1991) research studies.…”

Section: Introductionmentioning

confidence: 99%

Development of a Percutaneous Cerebrospinal Fluid Collection Technique in F-344 Rats and Evaluation of Cell Counts and Total Protein Concentrations

et al. 2006

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A simple technique for cerebrospinal fluid (CSF) collection was developed in F-344 rats. Cell counts and total protein concentrations were evaluated to assess sample quality. While the 50 to 70 µL samples of CSF collected on three different days showed a progressive decrease in the total erythrocyte and nucleated cell counts, no significant changes were observed in the total protein concentrations. Progressive decreases in the total erythrocyte count correlated positively with the decreases in volume of CSF collected. Our data suggest that collection of less than 50 µL of CSF will give a better quality of CSF in F-344 rats. This is the first report of cellular and protein parameters in the CSF of F-344 rats.

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Simultaneous determination of diazepam and its active metabolites in rat serum, brain and cerebrospinal fluid by high-performance liquid chromatography

Cited by 18 publications

References 10 publications

Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons after a Single Dose of Benzodiazepine Agonists

Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons after a Single Dose of Benzodiazepine Agonists

Relationship between cerebral pharmacokinetics and anxiolytic activity of diazepam and its active metabolites after a single intra‐peritoneal administration of diazepam in mice

Development of a Percutaneous Cerebrospinal Fluid Collection Technique in F-344 Rats and Evaluation of Cell Counts and Total Protein Concentrations

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