Pleiotropic effect of histamine H4 receptor modulation in the central nervous system.

The histamine H4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Recently, it has been reported the functional expression of H4R within neurons of the central nervous system, but their role has been poorly understood. The present study aimed to elucidate the physiopathological role of cerebral H4R in animal models by the intracerebroventricular administration of the H4R agonist VUF 8430 (20-40 µg per mouse). Selectivity of results was confirmed by the prevention of the effects produced by the H4R antagonist JNJ 10191584 (3-9 mg/kg p.o.). Neuronal H4R activation induced acute thermal antinociception, indicating that neuronal histamine H4R might be involved in the production of antinociception in the absence of an inflammatory process. An anxiolytic-like effect of intensity comparable to that exerted by diazepam, used as reference drug, was produced in the light-dark box test. VUF 8430 reversed the scopolamine-induced amnesia in the passive avoidance test and showed anorexant activity in food deprived mice. Conversely, the H4R activation did not modify the immobility time in the tail suspension test. Rotarod performance test was employed to demonstrate that the effects observed following the administration of VUF 8430 and JNJ 10191584 were not due to impaired motor function of animals. Furthermore, both compounds did not alter spontaneous mobility and exploratory activity in the hole board test. These results show the antinociceptive, antiamnesic, anxiolytic and anorexant effects induced by neuronal H4R agonism, suggesting that H4 modulators may have broader utility further the control of inflammatory and immune processes.

Combination of midazolam and a cyclooxygenase-2 inhibitor inhibits lipopolysaccharide-induced interleukin-6 production in human peripheral blood mononuclear cells.

CONTEXT: Interleukin-6 (IL-6) plays an important role in immune and inflammatory responses. Midazolam has been reported to modulate IL-6 response. Cyclooxygenase (COX) inhibitors, which are used together with midazolam in some patients undergoing surgery, also modulate it. We hypothesized that their combination results in eliciting the synergistical effect on the IL-6 response. OBJECTIVE: The aim of the present study was to evaluate the effect of the combination of midazolam and a COX inhibitor on IL-6 production. MATERIALS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and incubated with lipopolysaccharide (LPS), midazolam, and/or COX inhibitors, including indomethacin, SC-560, a COX-1 selective inhibitor, and NS-398, a COX-2 selective inhibitor. The supernatant concentrations of IL-6 and prostaglandins (PGs), including PGE2, PGF2α, PGD2, and 15-deoxy-Δ¹²,¹4-prostaglandin J2 (15dPGJ2) were measured. RESULTS: Midazolam had no effect on IL-6 production in the cells incubated for 12 h, and any COX inhibitors also had no effect. However, the combination of midazolam and NS-398 significantly inhibited it. Midazolam raised the concentration of 15dPGJ2 in the supernatant of the cells, but not the concentration of other PGs. DISSCUSSION AND CONCLUSION: The results in the present study demonstrated that the combination of midazolam and a COX-2 inhibitor inhibited LPS-induced IL-6 production in human PBMCs even if each drug separately did not have any effect on it. The finding suggests that their combination is effective against excessive IL-6 production such as severe inflammatory response and that the effect of midazolam on IL-6 production is possibly elicited via 15dPGJ2.

Discriminative stimulus properties of alprazolam.

RATIONALE: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. OBJECTIVE: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. METHODS: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40"-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. RESULTS: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), N-methyl-beta-carboline-3-carboxamide (FG-7142) and picrotoxin. CONCLUSIONS: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality.

Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo.

PURPOSE: This study evaluated the relationship of dose, plasma concentration, and time to the pharmacodynamics of zaleplon and zolpidem, 2 structurally distinct benzodiazepine receptor agonists. METHOD: Ten healthy male volunteers received single oral doses of placebo, 10 mg zaleplon, 20 mg zaleplon, 10 mg zolpidem, and 20 mg zolpidem in a double-blind, 5-condition crossover study, with 48 hours elapsing between trials. Plasma drug concentrations and pharmacodynamic effects were measured during the 8 to 24 hours after administration. RESULTS: Kinetics of zaleplon and zolpidem were not significantly related to dose. However, zaleplon had more rapid elimination (apparent elimination half-life [t1/2] of 1 hour) and higher apparent oral clearance (approximately 4300 mL/min) than zolpidem (t1/2, 2.0 to 2.2 hours; apparent oral clearance, 340 to 380 mL/min). Active treatments produced pharmacodynamic effects consistent with benzodiazepine agonist activity: self- and observer-rated sedation, impairment of digit symbol substitution test (DSST) performance, impaired memory, and increased electroencephalographic activity in the beta frequency range. The overall order of agonist potency was as follows: placebo < 10 mg zaleplon < 20 mg zaleplon < 10 mg zolpidem < 20 mg zolpidem; on a number of measures, 20 mg zaleplon was comparable to 10 mg zolpidem. Quantitative effects of zolpidem 20 mg far exceeded those of other treatments. Dynamic effects of both drugs were significantly related to plasma concentration. CONCLUSIONS: Benzodiazepine agonist effects of zaleplon and zolpidem were dose and concentration dependent. At the usual clinically effective hypnotic dose (10 mg of either drug), agonist effects of zolpidem exceeded those of zaleplon.

Hormonal modulation of benzodiazepines' actions on rat isolated uterus.

Effects of various benzodiazepines were investigated in ovariectomized rat isolated uterus which had been chronically pre-treated with different female sex hormones: oestrogen, progesterone and oestrogen + progesterone. Uteri obtained from all groups developed a spontaneous, rhythmic activity. The spontaneous activity observed in control uterus was either inhibited in a concentration-dependent manner by diazepam, 4'-chlorodiazepam, clonazepam or 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam ide (PK 11195), or was abolished in [Ca2+]o-free solution. Diazepam, 4'-chlorodiazepam, clonazepam and PK 11195 all caused a concentration-dependent relaxation of the [K+]o-pre-contracted uterus with the relative order of potency: PK 11195 > 4'-chlorodiazepam > diazepam > clonazepam. Administration of [Ca2+]o (1 microM to 10 mM) caused a concentration-dependent contraction of uterus, bathed in [Ca2+]o-free physiological salt solution obtained from different pre-treatment groups. Incubation with different concentrations (microM) of diazepam, 4'-chlorodiazepam, clonazepam and PK 11195 caused a decrease in response to [Ca2+]o-induced contraction in all groups of rat uteri. These results indicate that micromolar benzodiazepine binding sites exist in rat uterus. Diazepam, 4'-chlorodiazepam, clonazepam and PK 11195 caused relaxation of pre-contracted rat uterus and this effect may involve the inhibition of influx of [Ca2+]o and the relaxing effects of different benzodiazepines observed in this study can be modulated by pre-treatment with different female hormones.