Ambien online research references
uni-duesseldorf.de
Histaminergic neurons of the tuberomamillary nucleus display pacemaker properties; their firing rate is regulated according to behavioural state by gabaergic inhibition. Whole-cell recordings and single-cell RT-PCR from acutely isolated rat tuberomamillary neurons were used to characterize GABA -evoked currents and to correlate them with the expression pattern of 12 GABAA receptor subunits. We report differences in sensitivity to GABA and zinc as well as in the modulation of IPSC-decay times by zolpidem in histaminergic neurons expressing gamma-subunits at different levels. Immunocytochemistry and pharmacological analysis of whole-cell GABA-currents in these neurons revealed that all carry the gamma2-subunit protein and that all receptors contain at least one gamma-subunit. Neurons with different expression levels of gamma-subunits displayed a difference in cooperativity of GABA and zolpidem binding which we explain by the presence of one vs. two gamma-subunits in one receptor. Thus, we describe here native GABAA receptor function in relation to its stoichiometry.
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Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):15170-5. Epub 2002 Nov 01.
Altered kinetics and benzodiazepine sensitivity of a GABAA receptor subunit mutation [gamma 2(R43Q)] found in human epilepsy.
Bowser DN, Wagner DA, Czajkowski C, Cromer BA, Parker MW, Wallace RH, Harkin LA, Mulley JC, Marini C, Berkovic SF, Williams DA, Jones MV, Petrou S.
Department of Physiology, University of Melbourne, Victoria 3010, Australia.
The gamma-aminobutyric acid type A (GABA(A)) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA(A) receptor would be expected to cause neuronal hyperexcitability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA(A) gamma(2)-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA(A) receptor deactivation and increases the rate of desensitization, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus laevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from alpha(1)beta(2)gamma(2) or alpha(1)beta(2)gamma(2)(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem. These results provide evidence of impaired GABA(A) receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.
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Psychopharmacology (Berl). 2003 Jan;165(3):209-15. Epub 2002 Nov 06.
Discriminative stimulus effects of zolpidem in squirrel monkeys: role of GABA(A)/alpha1 receptors.
Rowlett JK, Spealman RD, Lelas S, Cook JM, Yin W.
Harvard Medical School, New England Regional Primate Research Center, One Pine Hill Drive, Box 9102, Southborough, MA 01772-9102, USA. james_rowlett
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hms.harvard.edu
RATIONALE: The discriminative stimulus effects of zolpidem in squirrel monkeys trained at doses greater than or equal to 3.0 mg/kg differ from those of conventional benzodiazepines (BZs), but the extent to which these effects reflect the selectivity of zolpidem for GABA(A)/alpha(1) receptors is not known. OBJECTIVES: The present study investigated the ability of GABA(A)/alpha(1)-preferring agonists to substitute for training doses of zolpidem greater than or equal to 3.0 mg/kg and the ability of GABA(A)/alpha(1)-preferring antagonists to block zolpidem's discriminative stimulus effects. METHODS: Squirrel monkeys were trained to discriminate intravenous injections of zolpidem (3.0 or 5.6 mg/kg) from saline and tested with BZ agonists differing in selectivity and efficacy at GABA(A)/alpha(1) receptors. Antagonism of the effects of zolpidem was studied using the GABA(A)/alpha(1)-preferring antagonists beta-carboline-3-carboxylate-t-butyl ester (beta-CCT) and 3-propyloxy-beta-carboline (3-PBC). RESULTS: Zolpidem and quazepam (GABA(A)/alpha(1)-preferring agonist) engendered full substitution for zolpidem, whereas CL 218,872 (GABA(A)/alpha(1)-preferring partial agonist) and the non-selective BZ agonists alprazolam and flunitrazepam engendered low and variable levels of zolpidem-lever responding (35-58%). Both beta-CCT and 3-PBC antagonized the discriminative stimulus effects of zolpidem in a surmountable fashion. CONCLUSIONS: Our findings provide evidence for a key role of GABA(A)/alpha(1) receptors in the discriminative stimulus effects of zolpidem at relatively high training doses, and suggest that selectivity and relatively high efficacy at GABA(A)/alpha(1) receptors is required for BZ agonists to reproduce these discriminative stimulus effects.
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Arzneimittelforschung. 2002;52(10):740-4.
Cerebral blood perfusion after treatment with zolpidem and flumazenil in the baboon.
Clauss RP, Dormehl IC, Kilian E, Louw WK, Nel WH, Oliver DW.
Nuclear Medicine Department, Medical University of Southern Africa, Medunsa, South Africa.
Previous studies have shown that zolpidem (CAS 82626-48-0) can lead to improved perfusion in damaged brain tissue. Zolpidem belongs to the imidazopyridine chemical class and it illicits its pharmacological action via the gamma-aminobutyric acid (GABA) receptor system through stimulation of particularly the omega 1 receptors and to a lesser extent omega 2 receptors. Previously it was reported that no cerebral blood flow effects were observed in normal baboons after treatment with zolpidem, whereas an asymmetric regional increase in cerebral blood flow was observed in a neurologically abnormal baboon. In this study, the effect of a combination of the benzodiazepine receptor antagonist flumazenil (CAS 78755-81-4) and zolpidem on brain perfusion was examined by the 99mTc-hexamethyl-propylene amine oxime (99mTc-HMPAO) split dose brain single photon emission computed tomography (SPECT). Four normal baboons and the neurologically abnormal baboon from the previous zolpidem study were examined. In the current study the asymmetric changes observed after zolpidem--only treatment in the abnormal baboon was attenuated by flumazenil intervention. A decreased brain blood flow was observed after combination treatment of zolpidem and flumazenil in the normal baboons. The involvement of the omega receptors is suggested by these results. Up- or down-regulation of omega receptors may also contribute to the observed responses in the abnormal baboon and a brain injured patient.
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