Modulation of [35S]TBPS binding by ligands with preferential affinity for benzodiazepine BZ1 sites in the cerebral cortex of newborn and adult rats. Rapid down-regulation of [3H]zolpidem binding to rat brain benzodiazepine receptors during flurazepam treatment. Differential effects of midazolam and zolpidem on sleep-wake states and epileptic activity in WAG/Rij rats. Effect of zolpidem on gamma-aminobutyric acid (GABA)-induced inhibition predicts the interaction of ethanol with GABA on individual neurons in several rat brain regions. Ambien online references

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RATIONALE: It has been suggested that different BZ (omega) receptor subtypes may mediate distinct behavioural effects of BZ receptor ligands. OBJECTIVE: The present study examined this hypothesis further. METHODS: The antagonism exerted by the selective BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor agonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed. RESULTS: beta-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (omega) receptor full agonist diazepam and the selective BZ(1) (omega(1)) receptor full agonist zolpidem against seizures produced by isoniazid, but beta-CCT failed to affect their action on seizures produced by pentylenetetrazole (PTZ), suggesting that BZ(2) (omega(2)) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, beta-CCT abolished the anxiolytic-like action of diazepam. In tests designed to investigate the central depressant activity of drugs, beta-CCT antagonized the sedative effects of diazepam and zolpidem, but failed to modify clearly the myorelaxant effects of diazepam. These differences may be related to the selectivity of beta-CCT for BZ(1) (omega(1)) sites as indicated by the preferential displacement of [(3)H]flumazenil in BZ(1) (omega(1))-enriched structures as compared to BZ(2) (omega(2))-enriched structures in the mouse. In in vitro experiments, beta-CCT antagonized the potentiation of the GABA-induced Cl(-) current produced by zolpidem in HEK cells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purkinje neurones, while it failed to modify the diazepam potentiation at either alpha(3)beta(2)gamma(2) or alpha(5)beta(3)gamma(2) receptor subtypes. CONCLUSION: These results are consistent with the hypothesis that BZ(1) (omega(1)) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.

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Eur J Pharmacol. 1995 Jun 23;290(1):37-47.
Modulation of [35S]TBPS binding by ligands with preferential affinity for benzodiazepine BZ1 sites in the cerebral cortex of newborn and adult rats.

Giorgi O, Lecca D, Cancedda E, Serra GP, Corda MG.

Department of Toxicology, University of Cagliari, Italy.

The present study was designed to compare the allosteric coupling between the Cl- channel of the GABAA receptor and the different benzodiazepine recognition site subtypes (BZ sites) in the cerebral cortex of newborn (5-day-old) and adult rats (90-day-old). To this aim, we reexamined the heterogeneity of cortical GABAA receptors in self- and cross-competition binding experiments using [3H]flunitrazepam and two ligands with higher affinity for benzodiazepine BZ1 sites relative to benzodiazepine BZ2 sites, the triazolopyridazine 3-methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo [4,3-b] pyridazine (CL 218,872) and the imidazopyridine N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]-pyridine-3-acetamide hemitartrate (zolpidem). Benzodiazepine BZ1 sites accounted for 52% of the total number of binding sites in adult rats, but were not detected in newborn rats. On the other hand, two classes of benzodiazepine BZ2 sites with high and low affinity for zolpidem were present in newborn and adult rats. These sites were designated as benzodiazepine BZ2H (high affinity for zolpidem, Kd approximately 150 nM) and benzodiazepine BZ2L (low affinity for zolpidem, Kd approximately 3000 nM). High densities of benzodiazepine BZ2H sites were measured in both newborn and adult rats (75% and 41% of the total number of [3H]flunitrazepam binding sites, respectively), whereas benzodiazepine BZ2L sites accounted for 25% and 7% of the total number of cortical sites in neonates and adults, respectively. Flunitrazepam, CL 218,872 and zolpidem inhibited in a concentration-dependent manner the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the convulsant site of cortical GABAA receptors in newborn and adult rats. The IC50 for flunitrazepam was about 3-fold greater in adults than in neonates. This rightward shift in the concentration-response curve may be due to a decrease with age in the intrinsic efficacy of flunitrazepam. In contrast, CL 218,872 and zolpidem were 4-fold more potent at inhibiting [35S]TBPS binding in adult rats relative to neonates. The different affinities of CL 218,872 and zolpidem for benzodiazepine BZ1 and BZ2 receptors may account, at least in part, for the age-related changes in their inhibitory potencies. These results demonstrate that benzodiazepine BZ2 sites mediate the modulation of [35S]TBPS binding by benzodiazepine recognition site ligands in the cerebral cortex of newborn rats. Further, benzodiazepine BZ2 sites may be involved in the inhibition of [35S]TBPS binding by flunitrazepam, CL 218,872 and zolpidem in the cerebral cortex of adult rats.

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Eur J Pharmacol. 1995 May 15;278(2):125-32.
Rapid down-regulation of [3H]zolpidem binding to rat brain benzodiazepine receptors during flurazepam treatment.

Wu Y, Rosenberg HC, Chiu TH.

Department of Pharmacology, Medical College of Ohio, Toledo 43699, USA.

In a previous study, it was found that down-regulation of benzodiazepine (BZ) binding in rats treated 4 weeks with flurazepam was relatively greater and more widespread when measured with [3H]zolpidem, a selective 'BZ1 receptor' ligand, than that measured with the non-selective ligand, [3H]flunitrazepam. In the present study, the time course for down-regulation of [3H]zolpidem binding was studied in rats treated with flurazepam. [3H]Zolpidem binding was also studied in rats given a midazolam treatment shown to cause tolerance. Rats were chronically treated with flurazepam for 1 or 2 weeks, or with midazolam for 3 weeks, then killed immediately after the treatment. Another group of rats was acutely treated with desalkyl-flurazepam and killed 30 min later. After 2 weeks of flurazepam treatment, the Bmax of [3H]zolpidem binding was decreased by 22% in cerebral cortex, 26% in cerebellum and 33% in hippocampus, with no change in the Kd in any region. After 1 week of flurazepam treatment, the Bmax was decreased by 23% in cerebellum and 14% in hippocampus, but not changed in cerebral cortex. The Kd was increased in cerebral cortex, but not in cerebellum or hippocampus. Neither the Bmax nor the Kd of [3H]zolpidem binding was affected by acute desalkyl-flurazepam treatment, or by 3 weeks of midazolam treatment. These results, in combination with previous findings, which showed no change in [3H]flunitrazepam binding after 1 or 2 week flurazepam treatment, and no change in cerebellum even after the 4 week treatment, may indicate a shift in BZ receptor subtypes in flurazepam-tolerant rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Pharmacol Biochem Behav. 1995 Aug;51(4):571-6.
Differential effects of midazolam and zolpidem on sleep-wake states and epileptic activity in WAG/Rij rats.

Depoortere H, Francon D, van Luijtelaar EL, Drinkenburg WH, Coenen AM.

Synthelabo Recherche (L.E.R.S.), Bagneux, France.

Hypnotic drugs are known to possess antiepileptic activity. Therefore, the effects of the benzodiazepine hypnotic midazolam (10 mg/kg) and the novel imidazopyridine hypnotic zolpidem (10 mg/kg) on sleep-wake states and on the number of spike-wave discharges were evaluated in WAG/Rij rats. Rats of this strain are considered to be a model for generalized absence epilepsy. Animals were implanted with chronic monopolar EEG electrodes and, after recovery from surgery, the EEG was recorded for 6 h during the dark period on 3 consecutive days. Sleep recordings were analyzed using Hjorth's parameters and number and duration of spike-wave discharges were visually determined. It was found that both drugs facilitated nonREM sleep at the cost of wakefulness. Both hypnotics also reduced the number and duration of spike-wave discharges. The initial decrease after midazolam, however, was followed by a rebound reflecting a poorer quality of vigilance expressed as an increase in spike-wave discharges. The strong antiabsence activity of zolpidem mimics that of midazolam and is well correlated with their equipotent hypnotic action and anticonvulsant effect in the isoniazid test.

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J Pharmacol Exp Ther. 1995 Apr;273(1):526-36.
Effect of zolpidem on gamma-aminobutyric acid (GABA)-induced inhibition predicts the interaction of ethanol with GABA on individual neurons in several rat brain regions.

Criswell HE, Simson PE, Knapp DJ, Devaud LL, McCown TJ, Duncan GE, Morrow AL, Breese GR.

Department of Psychiatry, University of North Carolina at Chapel Hill, USA.

Previous investigations have suggested a relationship between zolpidem binding within specific brain regions and the ability of ethanol or zolpidem to enhance gamma-aminobutyric acid (GABA)-induced inhibition. The purpose of the present study was to extend our electrophysiological analysis to additional brain sites with high levels of zolpidem binding. In the brain regions chosen, red nucleus and globus pallidus, GABA-induced inhibition was shown to be enhanced by either ethanol or zolpidem on some, but not all, neurons. These findings led to the hypothesis that the effect of zolpidem on GABA-induced inhibition would predict the action of ethanol on responses to GABA for that neuron. When zolpidem and ethanol were applied individually to the same neurons in the red nucleus and globus pallidus, those neurons sensitive to zolpidem enhancement of GABA also were sensitive to ethanol. Conversely, if zolpidem did not enhance responses to GABA, ethanol did not enhance responses to GABA at these brain sites. A similar relationship between the abilities of zolpidem and ethanol to enhance GABA-induced inhibition was obtained in 90% of the neurons studied in the medial septum/diagonal band and ventral pallidum. These studies provide further support for the contention that the zolpidem-sensitive GABAA-benzodiazepine isoreceptor also responds to ethanol. Finally, the expression of GABAA subunit mRNAs was analyzed by polymerase chain reaction from micropunches of several brain regions that contain zolpidem binding sites and exhibit sensitivity to ethanol. Polymerase chain reaction analysis proved more sensitive than in situ hybridization in the detection of receptor subunit mRNAs. Several subunits (alpha 1, alpha 2, alpha 3, beta 2, beta 3 and gamma 2) were common to all brain regions in which ethanol and zolpidem enhanced GABA responses. GABAA receptor alpha 4/5, alpha 6, beta 1, gamma 1, gamma 3 and delta subunits were not consistently expressed in association with the presence of zolpidem binding. These data are consistent with the view that one native GABAA receptor to which zolpidem binds, and on which ethanol acts, contains the GABAA receptor subunits alpha 1, beta 2 and gamma 2; however, the present investigation did not preclude the possibility that other subunit combinations can contribute to ethanol and zolpidem enhancement of responses to GABA.

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