Low tolerance and dependence liabilities of etizolam: molecular, functional, and pharmacological correlates.

The effects of prolonged exposure to and subsequent withdrawal of the thienotriazolobenzodiazepine etizolam on gamma-aminobutyric acid (GABA) type A receptor gene expression and function were compared with those of the benzodiazepine lorazepam. Exposure of rat hippocampal neurons in culture to 10 microM etizolam for 5 days reduced the amounts of alpha5 and gamma2S receptor subunit mRNAs, whereas etizolam withdrawal was associated with a persistent reduction in gamma2S mRNA and an increase in alpha2 and alpha3 mRNAs. Neither chronic exposure to nor withdrawal of etizolam affected the acute modulatory effects of etizolam or lorazepam on GABA-evoked Cl- current.

Plasma concentrations of anxiolytic neuroactive steroids in men with panic disorder.

Plasma concentrations of neuroactive steroids in men with panic disorder (PD) were measured to evaluate their relations to psychopathology both before and during treatment. Participants comprised 13 men with PD and 10 normal controls. Patients were evaluated while drug-free as well as after 1 and 2 months of paroxetine therapy.

Novel anellated pyrazoloquinolin-3-ones: synthesis and in vitro BZR activity.

A series of pyrazolo[4,3-c]pyrrolo[3,2-f]quinolin-3-one derivatives 6, 7a-c, 8a,b, 9a,b and 10-12 were synthesized as modified pyrazoloquinolinone analogs (PQs) and evaluated for their ability to inhibit radioligand to central and peripheral benzodiazepine receptors (BZRs) and their effect on GABA(A) alpha1beta2gamma2L receptors expressed in Xenopus laevis oocytes. Multistep synthesis starting from 5-nitroindole, via the Gould-Jacobs reaction to the quinoline nucleus, yielded key intermediates 9-chloro-3H-pyrrolo[3,2-f]quinoline-8-carboxylates. The reaction of the latter with methyl-hydrazine and various phenyl-hydrazines furnished the final compounds.

Household-based costs and benefits of vaccinating healthy children in daycare against influenza virus: results from a pilot study.

Background: Vaccinating children against influenza virus may reduce infections in immunised children and household contacts, thereby reducing the household-based cost associated with respiratory illnesses.

Objective: To evaluate the impact of influenza virus vaccination of daycare children on costs of respiratory illnesses of the children and their household contacts from the household and societal perspective.

Study Design: Cost analysis of data from a randomised controlled trial covering the period November to April of 1996-7 and 1998-9.

Structure-activity relationships and effects on neuroactive steroid synthesis in a series of 2-phenylimidazo[1,2-a]pyridineacetamide peripheral benzodiazepine receptors ligands.

A series of 36 imidazopyridineacetamides (2-37) were designed and synthesized to evaluate the effects of structural changes on the amide nitrogen at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include variations in the length and number of the alkyl groups as well as introduction of different aromatic, heteroaromatic, and conformationally constrained groups. The affinities of these compounds for CBRs and PBRs were determined, and the results indicate that bulkiness of the substituents, their branching, and length beyond an optimal value may cause hindrance to the ligand in its interaction with the receptor.

Neuroanatomical and pharmacological evidence for a functional interaction between GABAergic and NPY-Y1 transmission in the amygdala of Y1R/LacZ transgenic mice.

Several lines of evidence indicate that GABA and neuropeptide Y (NPY) are functionally coupled and may interact in the regulation of fear- and anxiety-induced behavior. Neuroanatomical studies demonstrated that GABA and NPY coexist in neurons of the amygdaloid complex and that NPY may directly modulate the activity of GABAergic neurons by stimulating Y1 receptors. By using a transgenic mouse model harboring a construct comprising the murine Y1 receptor gene promoter fused to a lacZ reporter gene (Y1R/LacZ mice), we showed that long-term treatment with positive (diazepam or abecarnil) or negative (FG7142) modulators of GABAA receptor function induced a marked increase or decrease, respectively, in Y1 receptor gene expression in the amygdala.

Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus.

An interaction with the GABA type A (GABA(A)) receptor has long been recognized as one of the main neurochemical mechanisms underlying many of the pharmacological actions of ethanol. However, more recent data have suggested that certain behavioral and electrophysiological actions of ethanol are mediated by an increase in brain concentration of neuroactive steroids that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Neuroactive steroids such as 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) are, in fact, potent and efficacious endogenous positive modulators of GABA(A) receptor function.

Inhibition by miltirone of up-regulation of GABAA receptor alpha4 subunit mRNA by ethanol withdrawal in hippocampal neurons.

Miltirone, a tanshinone isolated from the root of Salvia miltiorrhiza, has been characterized as a low-affinity ligand for central benzodiazepine receptors. We have now shown that this compound bound with low affinity (micromolar range) to central benzodiazepine recognition sites but did not interact with peripheral benzodiazepine receptors. It failed to potentiate Cl(-) currents induced by gamma-aminobutyric acid (GABA) both in Xenopus oocytes expressing recombinant human GABA(A) receptors and in cultured rat hippocampal pyramidal cells, but it inhibited the ability of diazepam to potentiate the effect of GABA in these systems.

Increased expression of the gene for the Y1 receptor of neuropeptide Y in the amygdala and paraventricular nucleus of Y1R/LacZ transgenic mice in response to restraint stress.

A sustained increase in the brain concentrations of neuroactive steroids was previously shown to induce Y1 receptor gene expression in the amygdala of Y1R/LacZ transgenic mice which harbour a construct comprising the murine Y1 receptor gene promoter and the lacZ reporter gene. We now investigated the effects of restraint stress on both the cerebrocortical concentrations of neuroactive steroids and Y1 receptor gene expression in the amygdala and hypothalamic paraventricular nucleus (PVN) of Y1R/LacZ transgenic mice. The cerebrocortical concentrations of allopregnanolone and allotetrahydrodeoxycorticosterone were significantly increased immediately after a 1-h exposure to restraint stress and had returned to control values within 30 min.

Plasma concentrations of anxiolytic neurosteroids in men with normal anxiety scores: a correlation analysis.

Neurosteroids are physiological regulators of anxiety in experimental animals, but there are no data for humans about the modulatory effects of the hormones on normal aspects of this emotional parameter. Plasma concentrations of four neurosteroids, pregnenolone, progesterone (PROG), allopregnanolone and tetrahydrodeoxycorticosterone, suggested to be major anxiety regulators in experimental animals, were measured in a group of 58 physically and psychologically normal adult male subjects. In parallel, trait (genotypical) and state (phenotypical) anxiety scores were measured by the State-Trait Anxiety Inventory.

Signal molecules and receptors in the differential development of cerebellum lobules. Acute effects of cisplatin on nitric oxide and glutamate systems in Purkinje cell population.

Three functionally correlated parameters, nitric oxide (NO), glutamate and NMDA receptors were analyzed through enzymehistochemical and immunohistochemical reactions. A single injection of cisplatin (cisPt) was administered to 10-day-old rats in order to study how Purkinje cells differentiation may be early changed by a mild injury due to the drug during postnatal cerebellar histogenesis. In comparison with age-matched control rats, a correlated decreasing expression of nitric oxide synthase (NOS), glutamate and NMDAR1 was observed in the Purkinje cells of lobules VI-VIII 6 h after the treatment.

Neurosteroid secretion in panic disorder.

Evidence that neurosteroids have anxiolytic effects in animal models of anxiety has suggested that alterations of neurosteroid secretion might be implicated in the pathogenetic mechanisms of anxiety disorders in humans. In 25 female patients with panic disorder (PD) and 11 healthy female controls, we measured plasma concentrations of progesterone (PROG), pregnenolone (PREG), allopregnanolone (3alpha,5alpha-tetrahydroprogesterone=3alpha,5alpha-THPROG), dehydroepiandrosterone (DHEA) and tetrahydrodeoxycorticosterone (3alpha,5alpha-THDOC) during a drug-free month and during the following month of paroxetine therapy. The neurosteroids were measured during the early follicular phase, the mid-luteal phase and the premenstrual phase of both months (days 7, 22 and 27 from the beginning of the cycle).

Cost-effectiveness of hepatitis B vaccination of prison inmates.

The purpose of this paper is to determine the cost-effectiveness of vaccinating inmates against hepatitis B. From the prison perspective, vaccinating inmates at intake is not cost-saving. It could be economically beneficial when the cost of a vaccine dose is 1.

Changes in expression of the neuropeptide Y Y1 receptor gene in the medial amygdala of transgenic mice during pregnancy and after delivery.

Long-term administration of progesterone or allopregnanolone was previously shown to increase Y1 receptor gene expression in the medial amygdala of Y1R/LacZ transgenic mice, which harbor a construct comprising the murine Y1 receptor gene promoter and a lacZ reporter. We have now investigated the effects of physiological fluctuations in the cerebrocortical concentrations of neuroactive steroids during pregnancy on Y1R/LacZ transgene expression by quantitative histochemical analysis of beta-galactosidase activity. Cerebrocortical concentrations of progesterone and its metabolites allopregnanolone and allotetrahydrodeoxycorticosterone were increased on day 18 of pregnancy and had returned to control values 2 days after delivery.

Nitric oxide synthase in the frog cerebellum: response of Purkinje neurons to unilateral eighth nerve transection.

When vestibular damage occurs, nitric oxide synthase (NOS) expression in rat cerebellar flocculus is affected. Since compensation for postural symptoms occurs and Purkinje cells play an important role in movement coordination and motor learning, we analyzed in situ the induction of NOS in the Purkinje cell population of the cerebellum (corpus cerebelli) of frog after unilateral transection of the eighth statoacoustic nerve to gain insight into the role of NO in neural plasticity after injury. Three days after neurectomy, the early effects induced NADPH diaphorase reactivity in most of the Purkinje cells on the ipsilateral side, while on the contralateral side the highest labeling was observed at 15 days.

A rapid method for obtaining finasteride, a 5alpha-reductase inhibitor, from commercial tablets.

To study the effects of allopregnanolone (AP) depletion on stress-induced dopamine changes in cortical dopamine, the 5alpha-reductase inhibitor finasteride on a gram-scale is required. Two procedures for the extraction of finasteride from tablets are outlined (method A and B). In method A, a suspension of powdered tablets was preliminary extracted with chloroform and the extracts dried and evaporated.

Cell death may regulate visual functionality in the retina of adults of the dipteran Ceratitis capitata.

The white eye mutation in the medfly Ceratitis capitata, like the homologous mutation in Drosophila melanogaster, was shown to impair visual function. Light and electron microscopy, combined with the DNA-end labelling histochemistry (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) technique), were used to investigate whether programmed cell death may contribute to the morpho-functional differences between the retina of adults from the white eye and wild type strains. Several photoreceptor nuclei in mature white eye flies appeared smaller and showed intensely Toluidine Blue-stained chromatin masses.