[Imidazopyridines, an alternative to benzodiazepines] Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABAA receptors. Benzodiazepine receptor binding of nonbenzodiazepines in vivo: alpidem, zolpidem and zopiclone. Expression patterns of gamma-aminobutyric acid type A receptor subunit mRNAs in primary cultures of granule neurons and astrocytes from neonatal rat cerebella. Ambien online references

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Schweiz Rundsch Med Prax. 1992 Apr 21;81(17):555-6.
[Imidazopyridines, an alternative to benzodiazepines]

[Article in French]

Dessibourg CA.

Centre EEG-EMG de diagnostic neurophysiologique, Hopital cantonal de Fribourg.

Imidazopyridines are a new class of molecules comprising so far a pure hypnotic agent--zolpidem, and an anxiolytic alpidem. The biochemical mode of action and the clinical characteristics are discussed with particular reference to benzodiazepines.

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Neuropharmacology. 1992 Jul;31(7):693-700.
Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABAA receptors.

Sanger DJ, Zivkovic B.

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

In a previous study, it was found that both the benzodiazepine hypnotic, midazolam, and the imidazopyridine hypnotic, zolpidem, which has selective affinity for a sub-population of omega (benzodiazepine, BZ) modulatory sites of GABA(A) receptors, produced similar decreases in rates of food-reinforced lever pressing in rats. However, during 10 days of repeated administration, marked tolerance developed to the depressant effect of midazolam but little tolerance developed with zolpidem. It was found in the present study that, with a within-subject design similar to that used previously, tolerance developed to the response rate-decreasing activity of the benzodiazepine, triazolam and the cyclopyrrolone, zopiclone but not to that of the triazolopyridazine, CL 218,872. In another experiment, using a between-groups design, tolerance developed to the effect of midazolam, even if the injections were not associated with daily test sessions, providing no evidence for a drug-environment interaction. The lack of tolerance to zolpidem was confirmed in two experiments. There was little indication of tolerance to the depressant effect of zolpidem, even after 19 days administration of daily doses, up to 30 mg/kg, a dose 10 times greater than that which completely suppressed responding. These results showed that the extent to which tolerance develops to the effects of drugs with affinity for omega (BZ) modulatory sites can show wide variations which may be related to differences in mechanisms of action.

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Brain Res Bull. 1992 Dec;29(6):905-8.
Benzodiazepine receptor binding of nonbenzodiazepines in vivo: alpidem, zolpidem and zopiclone.

Byrnes JJ, Greenblatt DJ, Miller LG.

Department of Pharmacology and Experimental Therapeutics and Psychiatry, Tufts University School of Medicine, Boston, MA.

Several classes of nonbenzodiazepine compounds, including imidazopyridines such as alpidem and zolpidem and cyclopyrrolones, e.g., zopiclone, have effects similar to benzodiazepines and may act at the benzodiazepine receptor in brain. We characterized the binding of these compounds to the benzodiazepine site in three brain regions using specific uptake of the high-affinity ligand [3H]Ro15-1788 (flumazenil). For alpidem, benzodiazepine binding was decreased in cortex and hippocampus with increasing drug dose. For zolpidem, receptor binding was reduced in cortex without a dose-response effect and no effect was observed on cerebellar binding. Zopiclone did not alter binding except for a decrease in binding at the lowest dose evaluated and an increase in binding above control at the highest dose. These data corroborate prior studies indicating that the imidazopyridines appear to act at the benzodiazepine receptor, but do not support receptor subtype selectivity of zolpidem. The limited effect of zopiclone except for increased binding at high doses is also consistent with prior studies suggesting that zopiclone acts at a site distinct from the benzodiazepine receptor.

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psychiatry.umsmed.edu

The present study examined the acute behavioral effects and abuse potential of three drugs commonly used to treat sleep disorders, trazodone, zolpidem and triazolam, and placebo in ten male volunteers with histories of alcohol and drug abuse. Trazodone (100, 200 and 300 mg), a triazolopyridine antidepressant, was included because antidepressants are being used more frequently to treat sleep disorders, but it is unclear whether they have a distinct behavioral pharmacologic profile relative to benzodiazepine hypnotics. Zolpidem (15, 30 and 45 mg), an imidazopyridine hypnotic, was tested because it is the most commonly prescribed hypnotic and purportedly has a unique benzodiazepine-receptor binding profile. Triazolam (0.25, 0.5 and 0.75 mg), a triazolobenzodiazepine hypnotic, was included as the standard component because previous laboratory studies have demonstrated that it has at least some abuse potential. Trazodone, zolpidem and triazolam generally produced comparable dose-related increases in scores on the PCAG scale of the ARCI, which suggests the doses tested were equivalent on some behavioral dimension. The effects of trazodone on subject-rated items thought to measure abuse potential (e.g., subject ratings of Willing to Take Again) were less than those observed with triazolam. Zolpidem and triazolam produced comparable effects on these measures. The highest dose of zolpidem, but not triazolam, increased ratings of Like Drug, Happy, Good Effects, Friendly, Elated, Carefree and Bad Effects. Triazolam and zolpidem produced dose-dependent impairment on all of the performance tasks. Trazodone impaired performance on some, but not all, of these tasks. Consistent with the pharmacokinetics of these compounds, the time-action functions of trazodone, zolpidem and triazolam were similar on these measures. These data suggest that trazodone has less abuse potential than triazolam, and may be a viable alternative to benzodiazepine hypnotics in individuals with histories of alcohol or drug abuse. By contrast, despite its unique neuropharmacological profile, the acute behavioral effects and abuse potential of zolpidem are comparable to those of triazolam.

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Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9344-8.
Expression patterns of gamma-aminobutyric acid type A receptor subunit mRNAs in primary cultures of granule neurons and astrocytes from neonatal rat cerebella.

Bovolin P, Santi MR, Puia G, Costa E, Grayson D.

Fidia-Georgetown Institute for the Neurosciences, Washington, DC.

Using a competitive polymerase chain reaction assay, we have quantitated the absolute amounts of mRNA encoding 14 distinct subunits of the gamma-aminobutyric acid type A (GABAA) receptor in primary cultures of rat cerebellar granule neurons and cerebellar astrocytes. We found that the total amount of GABAA receptor subunit mRNA in astrocytes was 2 orders of magnitude lower than in neuronal cells. Furthermore, granule cell cultures expressed all 14 different GABAA subunit mRNAs, while the astroglial cultures contained detectable amounts of all the subunits expressed by granule cells except the alpha 6 and the gamma 2L subunits. Of the alpha subunit family members, the alpha 1, alpha 5, and alpha 6 mRNAs were prominent in granule cells, while the alpha 1 and alpha 2 mRNAs were abundant in astrocytes. Of the beta receptor subunit mRNAs, the beta 1 and beta 3 mRNAs were abundantly expressed in both cultures. The gamma 2S and gamma 2L mRNAs constituted the great majority of gamma subunit mRNAs in neurons, while the gamma 1 subunit mRNA was the most abundant gamma subunit mRNA in astrocytes. When various allosteric modulators of GABAA receptors were tested electrophysiologically, methyl 6,7-dimethoxy-4-ethyl-beta-carboline- 3-carboxylate (DMCM) was the only one to modulate chloride currents elicited by GABA in a significantly different manner in granule cells (negative modulation) compared with astrocytes (positive modulation). The latter effect was previously observed in transiently expressed recombinant GABAA receptors containing a gamma 1 instead of a gamma 2 subunit. Our quantitative mRNA results suggest that an important molecular determinant responsible for the DMCM-positive modulatory effect on astroglial native GABAA receptors is the presence of the gamma 1 subunit in the receptor assembly.

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