Pharmacologic actions of subtype-selective and novel GABAergic ligands in rat lines with differential sensitivity to ethanol. Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem. Molecular and pharmacological characterization of native cortical gamma-aminobutyric acidA receptors containing both alpha1 and alpha3 subunits. Central benzodiazepine receptor occupancy by zolpidem in the human brain as assessed by positron emission tomography. Protracted treatment with diazepam reduces benzodiazepine1 receptor-mediated potentiation of gamma-aminobutyric acid-induced currents in dissociated rat hippocampal neurons. Ambien online references

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Pharmacol Biochem Behav. 1996 Mar;53(3):723-30.
Pharmacologic actions of subtype-selective and novel GABAergic ligands in rat lines with differential sensitivity to ethanol.

Wong G, Sarviharju M, Toropainen M, Matecka D, Korpi ER.

Biomedical Research Center, Alko Group Ltd., Helsinki, Finland.

Alcohol-nontolerant (ANT) rats, produced by selective breeding for high sensitivity to motor-impairing effects of ethanol, have a point mutation in the cerebellar gamma-aminobutyric acid type A (GABAA) receptor alpha 6 subunit, which has been proposed to underlie enhanced sensitivity to benzodiazepine agonists as well. We compared ANT and alcohol-tolerant (AT) rats using behavioral and neurochemical methods to assess the significance of alpha 6- and non alpha 6-containing GABAA receptor subtypes. Motor performance in a tilting plane test was largely unaffected by a type I benzodiazepine receptor-preferring agonist, zolpidem [1-10 mg/kg, intraperitoneally (IP)], partial benzodiazepine agonists bretazenil and ZG-63 (both at 40 mg/kg, IP), and a novel broad-spectrum anticonvulsant loreclezole (40 mg/kg, IP) in both ANT and AT rats. In contrast, diazepam (10 mg/kg, IP) impaired performance of the ANT but not AT animals. These data, supported by results from brain regional autoradiography of [3H]Ro15-4513 and membrane binding of [3H]ZG-63 and [35S]TBPS as influenced by these ligands, strongly suggest that only ligands with full agonist actions on mutant (ANT) but not wild-type (AT) alpha 6-containing GABAA receptors are able to produce motor impairment in the ANT rats.

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Eur J Pharmacol. 1996 Oct 10;313(1-2):35-42.
Comparison of the pharmacological profiles of the hypnotic drugs, zaleplon and zolpidem.

Sanger DJ, Morel E, Perrault G.

Synthelabo Recherche, CNS Research Department, Bagneux, France.

The BZ1 (omega 1)-selective compound, zolpidem, is a clinically effective hypnotic drug with a pharmacological profile which differs from those of benzodiazepine anxiolytics and hypnotics. Zaleplon (CL 284,846) has recently been described as a hypnotic agent which also has BZ1 (omega 1) receptor selectivity. The pharmacological effects of zolpidem and zaleplon were therefore compared in mice and rats. Both drugs blocked tonic convulsions induced in mice by pentylenetetrazole and electroconvulsive shock and clonic convulsions induced by isoniazid. Zaleplon was more potent than zolpidem but the maximal effect of zolpidem for increasing the latency to isoniazid-induced convulsions was greater than that of zaleplon. Little tolerance developed to the anticonvulsant effect of zaleplon against isoniazid-induced seizures following twice daily administration of 10 or 30 mg/kg for 10 days. Both compounds reduced locomotor activity and produced motor deficits in the rotarod and loaded grid tests in mice. However, while zaleplon produced all three effects at similar doses, zolpidem showed the greatest potency for reducing locomotion. Zaleplon and zolpidem also decreased locomotion and produced a rotarod deficit in rats. Again, the difference between the doses giving rise to these two effects was greater for zolpidem than for zaleplon. In a drug discrimination procedure using rats trained to discriminate a dose (5 mg/kg) of chlordiazepoxide, zaleplon produced partial substitution for chlordiazepoxide at doses which greatly reduced response rates. These results show that zaleplon and zolpidem have similar pharmacological profiles, presumably related to their BZ1 (omega 1) receptor selectivity. However, the difference between doses producing motor deficits (rotarod, loaded grid) and those giving rise to other effects (anticonvulsant, decreased locomotion) was greater for zolpidem than for zaleplon. This difference may be related to a greater in vivo intrinsic activity of zolpidem as indicated by the different efficacies of the two drugs to antagonise isoniazid-induced convulsions.

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J Biol Chem. 1996 Nov 1;271(44):27902-11.
Molecular and pharmacological characterization of native cortical gamma-aminobutyric acidA receptors containing both alpha1 and alpha3 subunits.

Araujo F, Tan S, Ruano D, Schoemaker H, Benavides J, Vitorica J.

Departamento Bioquimica, Bromatologia, y Toxicologia, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain.

We have investigated the existence, molecular composition, and benzodiazepine binding properties of native cortical alpha1-alpha3 gamma-aminobutyric acidA (GABAA) receptors using subunit-specific antibodies. The co-existence of alpha1 and alpha3 subunits in native GABAA receptors was demonstrated by immunoblot analysis of the anti-alpha1- or anti-alpha3-immunopurified receptors and by immunoprecipitation experiments of the [3H]zolpidem binding activity. Furthermore, immunodepletion experiments indicated that the alpha1-alpha3 GABAA receptors represented 54.7 +/- 5.0 and 23.6 +/- 3.3% of the alpha3 and alpha1 populations, respectively. Therefore, alpha1 and alpha3 subunits are associated in the same native GABAA receptor complex, but, on the other hand, these alpha1-alpha3 GABAA receptors from the cortex constitute a large proportion of the total alpha3 population and a relatively minor component of the alpha1 population. The pharmacological analysis of the alpha1- or alpha3-immunopurified receptors demonstrated the presence of two different benzodiazepine binding sites in each receptor population with high (type I binding sites) and low (type II binding sites) affinities for zolpidem and Cl 218,872. These results indicate the existence of native GABAA receptors possessing both alpha1 and alpha3 subunits, with alpha1 and alpha3 subunits expressing their characteristic benzodiazepine pharmacology. The molecular characterization of the anti-alpha1-anti-alpha3 double-immunopurified receptors demonstrated the presence of stoichiometric amounts of alpha1 and alpha3 subunits, associated with beta2/3, and gamma2 subunits. The pharmacological analysis of alpha1-alpha3 GABAA receptors demonstrated that, despite the fact that each alpha subunit retained its benzodiazepine binding properties, the relative proportion between type I and II binding sites or between 51- and 59-61-kDa [3H]Ro15-4513-photolabeled peptides was 70:30. Therefore, the alpha1 subunit is pharmacologically predominant over the alpha3 subunit. These results indicate the existence of active and nonactive alpha subunits in the native alpha1-alpha3 GABAA receptors from rat cortex.

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Eur J Pharmacol. 1996 Jan 4;295(1):35-44.
Central benzodiazepine receptor occupancy by zolpidem in the human brain as assessed by positron emission tomography.

Abadie P, Rioux P, Scatton B, Zarifian E, Barre L, Patat A, Baron JC.

INSERM U. 320, University of Caen, France.

The central benzodiazepine receptor occupancy by zolpidem in man is unknown. The present study used positron emission tomography (PET) and [11C]flumazenil to assess in five healthy volunteers, central benzodiazepine receptor occupancy in brain regions with high receptor densities 1 h following an acute oral administration of twice the usual hypnotic dose of zolpidem (20 mg). Receptor occupancy was measured in five discrete structures (middle frontal gyrus, middle temporal gyrus, posterior occipital cortex, lateral parietal cortex, and cerebellar cortex) and in a large neocortical area as the fractional change in the [11C]flumazenil bound/free ratio for the interval 15-40 min post-administration of the radiotracer. The free-radioligand concentration was estimated from the pons, a reference structure virtually devoid of central benzodiazepine receptor. With individual pons values, mean occupancy was about 21% but with spurious inter-subject variability. With pons values averaged across the five subjects and separately for control and treated condition, the occupancy was (mean +/- S.D.) 27 +/- 11% for the whole neocortex, and ranged from 26 to 29% in the five discrete structures (P < 0.01). By showing hypnotic effect at moderate occupancies, this study directly provides evidence for the full-agonist properties of zolpidem in human.

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J Pharmacol Exp Ther. 1996 Dec;279(3):1092-9.
Protracted treatment with diazepam reduces benzodiazepine1 receptor-mediated potentiation of gamma-aminobutyric acid-induced currents in dissociated rat hippocampal neurons.

Itier V, Granger P, Perrault G, Depoortere H, Scatton B, Avenet P.

Synthelabo Recherche, Central Nervous System Research Department, Bagneux, France.

Tolerance to benzodiazepines (BZs) is thought to involve alterations of the gamma-aminobutyric acid (GABA)A receptor as a result of the prolonged occupancy of its modulatory BZ recognition site. We used the whole-cell patch-clamp technique to compare the functional and pharmacological properties of GABAA receptors in acutely dissociated hippocampal neurons from the control or diazepam-tolerant rats. Administration of diazepam (15 mg/kg p.o.) twice a day for 10 days induced tolerance as demonstrated by the decreased potency of acute diazepam i.p. injections to protect against pentylenetetrazole-induced clonictonic convulsions (10.5% of tolerant rats protected by 0.1 mg/kg of diazepam against 55% of nontreated rats, 48 hr after the last dose of the chronic treatment). The specific current induced by 1 microM GABA in acutely dissociated hippocampal neurons 48 hr after withdrawal (10.5 +/- 1.3 microA/cm2) was similar to that observed in the control rats (8.7 +/- 0.8 microA/cm2). The EC50 value for GABA was unchanged by the chronic treatment [6.3 (5.4-7.1) and 7.5 (6.2-8.7) microM in neurons from the control and treated rats, respectively]. The potency of the nonselective allosteric modulator diazepam to stimulate Cl- currents was identical in cells from treated rats [EC50 values of 25 (20-30) and 34 (26-41) nM in the control and treated rats, respectively; P < .05], but the potency of the selective BZ1-site ligand zolpidem was decreased [EC50 values of 99 (88-111) and 267 (221-313) nM in the control and treated rats, respectively; P < .05]. The maximal potentiation of the GABA-induced current was significantly decreased with diazepam (maximal potentiation: 168.0 +/- 16.2 and 124.0 +/- 8.9% in the control and treated rats, respectively). These results suggest that tolerance to diazepam is accompanied in hippocampal neurons by a decrease in BZ1 binding sites and in the functional coupling of BZ/GABA recognition sites.

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