Marked variation in diazepam sensitivity in Swiss albino mice

Wong, Peter T.-H.; Yoong, Y. L.; Gwee, M.C.E.

doi:10.1016/0024-3205(86)90281-x

Cited by 10 publications

(3 citation statements)

References 13 publications

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“…4) was needed to produce an observable effect in mice. It is well established that mice are only sedated at much higher doses than humans, even with strong sedative hypnotics such as the benzodiazepines [39].…”

Section: Discussionmentioning

confidence: 99%

Acute Antidepressant-Like and Antianxiety-Like Effects of Tryptophan in Mice

Wong

Ong

2001

Pharmacology

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The antidepressant-like, antianxiety-like and sedative effects of tryptophan (TRP), in the absence and presence of p-chlorophenylalanine (p-CPA), and melatonin were studied in mice using the forced-swimming test, open-field test and activity cage, respectively. Single-dose TRP caused an antidepressant-like effect dose dependently up to 125 mg/kg. No significant effect was observed, however, when the TRP dose was increased to 250 mg/kg, i.e. a reversal of effect occurred at high dose. With p-CPA pretreatment, the effects observed at 125 and 250 mg/kg TRP were similar to those obtained at 50 and 125 mg/kg without p-CPA pretreatment, respectively. Melatonin also caused an antidepressant-like effect in a similar manner, but appeared to be less potent than TRP. These results strongly indicate that the antidepressant-like effect of TRP was due to its conversion to 5-hydroxytryptamine (5-HT). An antianxiety-like effect was observed for TRP only at 250 mg/kg dose together with p-CPA pretreatment, while no sedative effect was observed at all. In contrast, melatonin did not produce any antianxiety-like effect, but produced sedation at 200 mg/kg dose. It may be concluded that the antianxiety-like effect of TRP is unrelated to 5-HT and melatonin formation, but associated with TRP itself or, perhaps, with other anxiolytic metabolites.

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Section: Discussionmentioning

confidence: 99%

Acute Antidepressant-Like and Antianxiety-Like Effects of Tryptophan in Mice

Wong

Ong

2001

Pharmacology

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“…Since both drugs interact with GABAA/benzodiazepine receptors, one might hypothesize that these traits are genetically related. Many studies reporting differences in sensitivities to drugs acting at GABAg/benzodiazepine receptors suggest that genetic or other constitutional factors contribute to the pharmacological actions of benzodiazepines and related drugs in humans and in laboratory animals (Mandelli et aL, 1978;Robertson, 1979;Hall and Zisook, 1981;Schweri et al, 1983;File, 1983;Wong et al, 1986). Thus, the C57BL/6J and A/J mouse strains might be particularly useful in investigating the genotypic substrate of responses to benzodiazepine drugs as well as exploratory behaviors in a novel environment.…”

Section: Introductionmentioning

confidence: 96%

Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains

et al. 1995

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Recombinant inbred (RI) strains derived from the C57BL/6J and A/J mouse strains were used for behavioral studies designed to estimate the number and location of chromosomal loci responsible for anxiety-related behaviors and differential sensitivity to agonists and inverse agonists of the gamma-aminobutyric acidA (GABAA)/benzodiazepine receptor complex. The phenotypes of the parental inbred strains and of 28 RI strains were characterized for the number of transitions in the light<-->dark exploratory model, anxiolytic response to diazepam, vertical and ambulatory activities in an open field, and sensitivity to the convulsant properties of methyl-beta-carboline-3-carboxylate (beta-CCM). The strain distribution patterns and estimates of the minimal number of loci obtained for each trait suggest that multiple chromosomal loci contribute to differences in anxiety-related behavioral phenotypes and the behavioral responses to diazepam and beta-CCM between C57BL/6J and A/J mice. The best probabilities of linkage were found between the variables characterizing response to diazepam and loci on chromosomes 1 (Xmv-41) and 10 (D10Mit2) and between the sensitivity to the convulsant actions of beta-CCM and locus D15Mit5 on chromosome 15.

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“…In order to compare the observed effects of clozapine on RA catabolism with other psychotropic drugs, we next tested the effects of the antidepressants citalopram and sertraline, the benzodiazepine diazepam and the stimulant modafinil on RA catabolism, using equally high concentrations, including concentrations above therapeutically relevant tissue levels (see Supplementary Table 3 for estimated brain concentrations) [57][58][59][60][61]. Neither of the tested compounds affected the degradation of RA in mouse cortex-derived synaptosomes to the extent of clozapine (Fig.…”

Section: Impact Of Other Psychotropic Drugs On Cerebral Ra Catabolismmentioning

confidence: 99%

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

et al. 2020

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The atypical antipsychotic clozapine is one of the most potent drugs of its class, yet its precise mechanisms of action remain insufficiently understood. Recent evidence points toward the involvement of endogenous retinoic acid (RA) signaling in the pathophysiology of schizophrenia. Here we investigated whether clozapine may modulate RA-signaling. Effects of clozapine on the catabolism of all-trans RA (at-RA), the biologically most active metabolite of Vitamin A, were assessed in murine and human brain tissue and peripheral blood-derived mononuclear cells (PBMC). In patients with schizophrenia with and without clozapine treatment and matched healthy controls, at-RA serum levels and blood mRNA expression of retinoidrelated genes in PBMCs were quantified. Clozapine and its metabolites potently inhibited RA catabolism at clinically relevant concentrations. In PBMC-derived microsomes, we found a large interindividual variability of the sensitivity toward the effects of clozapine. Furthermore, at-RA and retinol serum levels were significantly lower in patients with schizophrenia compared with matched healthy controls. Patients treated with clozapine exhibited significantly higher at-RA serum levels compared with patients treated with other antipsychotics, while retinol levels did not differ between treatment groups. Similarly, in patients without clozapine treatment, mRNA expression of RA-inducible targets CYP26A and STRA6, as well as at-RA/retinol ratio, were significantly reduced. In contrast, clozapine-treated patients did not differ from healthy controls in this regard. Our findings provide the first evidence for altered peripheral retinoid homeostasis in schizophrenia and suggest modulation of RA catabolism as a novel mechanism of action of clozapine, which may be useful in future antipsychotic drug development.

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Marked variation in diazepam sensitivity in Swiss albino mice

Cited by 10 publications

References 13 publications

Acute Antidepressant-Like and Antianxiety-Like Effects of Tryptophan in Mice

Acute Antidepressant-Like and Antianxiety-Like Effects of Tryptophan in Mice

Genetic analysis of anxiety-related behaviors and responses to benzodiazepine-related drugs in AXB and BXA recombinant inbred mouse strains

Clozapine modulates retinoid homeostasis in human brain and normalizes serum retinoic acid deficit in patients with schizophrenia

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