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  • 1
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In addition to investigating sexual function in rats that display normal ejaculatory behaviour, studying rats that are either ‘hyposexual’ or ‘hypersexual’ may provide important insights into the aetiology of ejaculatory dysfunctions in men, such as premature and retarded ejaculation. To this end, rats were matched into groups of ‘sluggish’, ‘normal’ and ‘rapid’ ejaculators based on their ejaculation frequencies displayed in a series of weekly sexual behaviour tests. Selecting rats on this parameter revealed large and stable differences in other parameters of sexual behaviour as well, including ejaculation latency and mount frequency but not intromission frequency and mount latency, putative indices of sexual motivation. Neuroanatomically, Fos immunoreactivity as a measure of neuronal activation was increased in rapid ejaculators compared with sluggish ejaculators in ejaculation-related brain areas, presumably associated with the differences in ejaculatory behaviour. Although the total number of oxytocin neurones within subregions of the hypothalamus did not differ between groups, in the supraoptic nucleus of the hypothalamus more oxytocin neurones were activated in rapid ejaculators compared with the other groups. Apart from the differences observed in ejaculatory behaviour, groups did not differ with respect to their locomotor activity and approach-avoidance behaviour as measured in the elevated plus-maze. Finally, apomorphine-induced stereotypy was similar in sluggish and rapid ejaculators, suggesting no large differences in dopamine susceptibility. Altogether, the present results suggest stable differences in male rat ejaculatory behaviour. Further exploring the neurobiological mechanisms underlying these differences may be a promising approach to gain insights into the aetiology of sexual dysfunctions such as premature, retarded or an-ejaculation.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-904X
    Keywords: midazolam ; epilepsy ; functional adaptation ; pharmacodynamics ; operational model of agonism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A mechanism-based model is proposed for the analysis of adaptive changes in the pharmacodynamics of benzodiazepines in vivo. Methods. The pharmacodynamics of midazolam was studied in the kindling model of experimental epilepsy. Concentration-EEC effect data from kindled rats and their controls were fitted to the operational model of agonism. A stepwise procedure was used, allowing changes in the parameters efficacy (τ) and tissue maximum (Em) either separately or in combination. The results were compared to data obtainedin vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEC effect was non-linear. In kindled rats the maximum EEC effect was reduced by 27± 8.3µV from the original value of 94± 4.4µV. Analysis on the basis of the operational model of agonism showed that this decrease could be explained by a difference in the parameter system maximum (Em) rather than efficacy (τ). In the in vitro receptor binding assay no changes in density, affinity or functionality of the benzodiazepine receptor were observed, consistent with the lack of a change in efficacy (τ). Conclusions. The operational model of agonism provides a mechanistic basis to characterise adaptive changes in the pharmacodynamics of midazolam.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-904X
    Keywords: benzodiazepines ; pharmacokinetics ; EEG ; operational model of agonism ; receptor binding ; muscimol-induced Cl−uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A mechanism-based model is applied to analyse adaptivechanges in the pharmacodynamics of benzodiazepines upon chronictreatment in rats. Methods. The pharmacodynamics of midazolam was studied in ratswhich received a constant rate infusion of the drug for 14 days, resultingin a steady-state concentration of 102 ± 8 ng·ml−1. Vehicle treated ratswere used as controls. Concentration-EEG effect data were analysed onbasis of the operational model of agonism. The results were comparedto data obtained in vitro in a brain synaptoneurosomal preparation. Results. The relationship between midazolam concentration and EEGeffect was non-linear. In midazolam pre-treated rats the maximum EEGeffect was reduced by 51 ± 23 μV from the original value of 109 ±15 μV in vehicle treated group. Analysis of this change on basis ofthe operational model of agonism showed that it can be explained bya change in the parameter tissue maximum (Em) rather than efficacy(τ). In the in vitro studies no changes in density, affinity or functionalityof the benzodiazepine receptor were observed. Conclusions. It is concluded that the observed changes in theconcentration-EEG effect relationship of midazolam upon chronic treatmentare unrelated to changes in benzodiazepine receptor function.
    Type of Medium: Electronic Resource
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