Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons. Subtle changes in residue 77 of the gamma subunit of alpha1beta2gamma2 GABAA receptors drastically alter the affinity for ligands of the benzodiazepine binding site. Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens. Adeno-associated virus (AAV) vector antisense gene transfer in vivo decreases GABA(A) alpha1 containing receptors and increases inferior collicular seizure sensitivity. L-701,324, a glycine/NMDA receptor antagonist, blocks the increase of cortical dopamine metabolism by stress and DMCM. Ambien online references

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J Neurophysiol. 1997 Apr;77(4):1924-38.
Differential epilepsy-associated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons.

Gibbs JW 3rd, Shumate MD, Coulter DA.

Department of Anatomy, Medical College of Virginia, Richmond 23298-0599, USA.

Alterations in GABAergic function associated with the development of temporal lobe epilepsy (TLE) were examined with the use of patch-clamp recording techniques in dentate granule (DG) and CA1 neurons acutely isolated from control and spontaneously epileptic rats in which TLE was elicited by pilocarpine injection 3-17 wk before use. The maximal efficacy of gamma-aminobutyric acid (GABA) in activating whole cell GABA currents increased significantly in epileptic DG neurons relative to controls. This efficacy increase was due to a 78% enhancement in the functional capacitance-normalized GABA(A) receptor (GABA(A)R) current density in epileptic DG neurons. Increased DG GABA(A)R current density was not accompanied by alterations in GABA potency (EC50). However, the maximal sensitivity of DG GABA-evoked currents to blockade by zinc increased 190% in epileptic neurons. Augmentation of epileptic DG neuron GABA-evoked currents by the broad-spectrum anticonvulsant benzodiazepine clonazepam (100 nM) was enhanced 114% relative to controls, whereas augmentation by the benzodiazepine, (BZ1)-selective agonist zolpidem (100 nM) was decreased by 66%. In contrast to DG neurons, maximal efficacy of GABA in activating GABA currents decreased in epileptic CA1 neurons relative to controls, due to a 52% decrease in functional capacitance-normalized GABA(A)R current density. This altered efficacy of GABA was accompanied by an increased GABA potency (GABA EC50 was 35.8 and 24.5 microM in control and epileptic neurons, respectively). Sensitivity of GABA-evoked currents to blockade by zinc was unchanged in epileptic CA1 neurons, whereas clonazepam (100 nM) augmentation of CA1 GABA-evoked currents decreased 81% relative to controls. These regionally distinct epilepsy-associated modifications in hippocampal GABAergic function may be due to discrete structural alterations in postsynaptic GABA(A)Rs accompanying epileptogenesis, could be therapeutically important, and undoubtedly could contribute to the enhanced limbic excitability underlying TLE.

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J Biol Chem. 1997 May 2;272(18):11799-804.
Subtle changes in residue 77 of the gamma subunit of alpha1beta2gamma2 GABAA receptors drastically alter the affinity for ligands of the benzodiazepine binding site.

Buhr A, Baur R, Sigel E.

Department of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.

Recombinant alpha1beta2gamma2 gamma-aminobutyric acid type A (GABAA) receptors were functionally expressed in Xenopus oocytes. Upon the mutation F77L, diazepam and Ro 15-1788 retained the ability to interact with the benzodiazepine binding site, but zolpidem lost this ability. To quantify these data, radioligand binding experiments were performed using membrane preparations of transiently transfected human embryonic kidney 293 cells. The amino acid gamma77, phenylalanine, was also mutated to tyrosine, tryptophan, and isoleucine. Although there was little effect on Ro 15-1788 binding upon mutation to tyrosine, the loss in affinity for diazepam was from 12 to 2,720 nM. The change to leucine, in contrast, resulted in little change in the diazepam affinity, whereas there was a strongly reduced affinity for zolpidem from 17 to 4,870 nM and for methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) from 1.9 to 1,780 nM, respectively. The change to tryptophan resulted in two-phasic displacement curves, and only about 50% of the [3H]flunitrazepam binding could be displaced by zolpidem, DMCM, and Ro 15-1788, respectively, whereas midazolam and diazepam still resulted in 100% displacement, indicating the presence of two sites upon expression of this mutant receptor. Functional expression in Xenopus oocytes showed that all mutant channels displayed a comparatively small change (<4.3-fold) in their apparent agonist affinity and that these channels could still be functionally modulated by ligands of the benzodiazepine binding site. We conclude that subtle changes in gammaF77 drastically affect benzodiazepine pharmacology and that this residue probably interacts directly with most ligands of the benzodiazepine binding site and therefore defines part of the benzodiazepine binding pocket.

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Arch Pathol Lab Med. 1997 Apr;121(4):392-4.
Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

Piergies AA, Sainati S, Roth-Schechter B.

Evanston Hospital, Clinical Pharmacology Unit, IL 60201, USA.

OBJECTIVE: To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. DESIGN: Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). SETTING: Clinical Pharmacology Unit within a teaching hospital. MAIN OUTCOME MEASURES: Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. RESULTS: Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. CONCLUSIONS: These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

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Brain Res. 1997 May 9;756(1-2):76-83.
Adeno-associated virus (AAV) vector antisense gene transfer in vivo decreases GABA(A) alpha1 containing receptors and increases inferior collicular seizure sensitivity.

Xiao X, McCown TJ, Li J, Breese GR, Morrow AL, Samulski RJ.

Gene Therapy Center, University of North Carolina at Chapel Hill, 27599, USA.

In the inferior colliculus, adeno-associated virus (AAV) vectors are capable of gene transfer and stable, long-term expression, but it remained to be shown if this in vivo gene transfer could alter focal seizure sensitivity in the inferior colliculus. Because GABA receptors directly modulate inferior collicular seizures, AAV vectors were constructed with a cytomegalovirus (CMV) promoter and a truncated, human GABA(A) alpha1 cDNA in both the sense and antisense orientations. Seven days after collicular microinjection of the sense vectors (1 microl; 3 x 10(9) particles/microl), neurons exhibited GABA(A) alpha-like immunoreactivity in amounts far exceeding endogenous concentrations. Unilateral or bilateral sense vector infusion had no effect on inferior collicular seizure parameters or on [3H]zolpidem binding. In contrast, bilateral infusion of the antisense AAV-GABA(A) alpha1 vector (1 microl; 3 x 10(8) particles/microl) caused a 137% increase in the seizure duration. Moreover, unilateral antisense vector infusion produced a localized, 48% decrease in [3H]zolpidem binding. Thus, in the inferior colliculus, antisense AAV-CMV vectors can reduce a specific receptor subunit protein and change receptor function that directly influences in vivo seizure sensitivity.

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Eur J Pharmacol. 1997 May 20;326(2-3):127-32.
L-701,324, a glycine/NMDA receptor antagonist, blocks the increase of cortical dopamine metabolism by stress and DMCM.

Hutson PH, Barton CL.

MSD Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK. Peter_Hutson

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