Recent developments in the behavioral pharmacology of benzodiazepine (ω) receptors: Evidence for the functional significance of receptor subtypes

doi:10.1016/0149-7634(94)90049-3

Neuroscience & Biobehavioral Reviews

Volume 18, Issue 3, Autumn 1994, Pages 355-372

https://doi.org/10.1016/0149-7634(94)90049-3 Get rights and content

Abstract

Recent research in molecular biology has demonstrated the complexity of GABA_A receptors and shown that benzodiazepine (BZ-ω) receptor subtypes have a structural reality. It is therefore appropriate to ask whether the different pharmacological effects produced by benzodiazepines (anticonvulsant activity, anxiety reduction, motor incoordination, learning deficits, characteristic discriminative stimulus effects, tolerance and dependence) are associated with activity at different receptor subtypes. The present paper reviews the literature dealing with the behavioral effects of novel BZ (ω) receptor ligands relevant to the question of the functional significance of the BZ₁ (ω₁) and BZ₂ (ω₂) receptor subtypes. The only drugs currently available with a considerable degree of selectivity are alpidem and zolpidem. These compounds have relatively high affinity for GABA_A receptors containing the α₁ subunit (corresponding to the BZ₁ (ω₁) subtype) and very low affinity for receptors with the α₅ subunit (corresponding to one type of BZ₂ (ω₂) receptor). Pharmacological effects observed with these, and other, less selective compounds allow several tentative conclusions to be drawn: (a) Little is known of the role of subtype selectivity in anxiolytic or amnestic effects but compounds with low intrinsic activity may reduce anxiety without giving rise to sedation or motor incoordination and BZ₁ (ω₁) selective drugs appear to disrupt memory only at sedative doses; (b) Selectivity for BZ₁ (ω₁) receptors may be associated with sleep-inducing activity but not with motor incoordination, suggesting that BZ₂ (ω₂) receptors may be of particular importance in mechanisms of muscle relaxation; (c) The discriminative stimulus effects of different BZ (ω) receptor ligands are not identical and differences may be related to receptor selectivity; (d) Compounds with BZ₁ (ω₁) selectivity and compounds with low intrinsic activity produce little or no tolerance and dependence. A wider range of selective compounds will be necessary to investigate these factors in detail and many different pharmacological profiles can be expected from drugs with selectivity and different levels of intrinsic activity.

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^☆: This paper is based on a keynote lecture presented at the Second Annual International Behavioral Neuroscience Society Conference held in Clearwater Beach, Florida, USA, from April 22–25, 1993.

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ArticleRecent developments in the behavioral pharmacology of benzodiazepine (ω) receptors: Evidence for the functional significance of receptor subtypes☆

Abstract

Pharmacol. Ther.

Neuroscience

Mol. Brain Res.

Brain Res.

J. Biol. Chem.

Pharmacol. Biochem. Behav.

Br. J. Anaesth.

Eur. J. Pharmacol.

Biol. Psychol.

Trends Pharmacol. Sci.

Lancet

Eur. J. Pharmacol. Mol. Pharmacol. Sect.

Brain Res.

Eur. J. Pharmacol.

Neurosci. Biobehav. Rev.

Neurosci. Biobehav. Rev.

Pharmacol. Biochem. Behav.

Prog. Neurobiol.

Eur. J. Pharmacol.

Life Sci.

Neuropharmacology

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Life Sci.

FEBS

Brain Res.

Pharmacol. Biochem. Behav.

Life Sci.

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

A comparative study of the interaction of alcohol with alpidem, lorazepam and placebo in normal subjects

Int. Clin. Psychopharmacol.

Discriminative stimulus properties of the benzodiazepine partial agonist β-carbolines abecarnil and ZK 95962: A comparison with chlordiazepoxide

Behav. Pharmacol.

The mechanism of action of alpidem

Pharmacological profile of zolpidem at benzodiazepine receptors and electrocorticogram in rats

Naunyn Schemiedeberg's Arch. Pharmacol.

Drug discrimination and drug stimulus generalization with anxiolytics

Drug Dev. Res.

Differential generalisation to pentobarbital in rats trained to discriminate lorazepam, chlordiazepoxide, diazepam, or triazolam

Psychopharmacology

Comparison of the daytime sleep and performance effects of zolpidem vs. triazolam

Psychopharmacology

The first double-blind, placebo-controlled trial of a partial benzodiazepine agonist abecarnil (ZK 112–119) in generalised anxiety disorder

Psychopharmacol. Bull.

The sedative-hypnotic properties of quazepam, a new hypnotic agent

Arzneim-Forsch/Drug Res.

In vivo interaction of zolpidem with central benzodiazepine binding sites (as labelled by 3H-Ro 15–1788) in the mouse brain. Preferential affinity of zolpidem for the ω1 (BZD1) subtype

J. Pharmacol. Exp. Ther.

Comparative in vivo and in vitro regional selectivity of central ω (BZ) modulatory site ligands as displacers of [3H]flumazenil binding in the rat CNS

J. Pharmacol. Exp. Ther.

Identification and immunohistochemical mapping of GABAA receptor subtypes containing the δ-subunit in rat brain

FEBS Lett.

Comparison of the effects of zolpidem and triazolam on memory functions, psychomotor performances, and postural sway in healthy subjects

J. Clin. Psychopharmacol.

[3H]-propyl β-carboline-3-carboxylate as a selective radioligand for the BZ1 benzodiazepine receptor subclass

J. Neurochem.

Interaction of convulsive ligands with benzodiazepine receptors

Science

The comparative effects of benzodiazepines, progabide and PK 9084 on acquisition of passive avoidance in mice

Psychopharmacology

Article
Recent developments in the behavioral pharmacology of benzodiazepine (ω) receptors: Evidence for the functional significance of receptor subtypes☆

In vivo interaction of zolpidem with central benzodiazepine binding sites (as labelled by ³H-Ro 15–1788) in the mouse brain. Preferential affinity of zolpidem for the ω₁ (BZD₁) subtype

Comparative in vivo and in vitro regional selectivity of central ω (BZ) modulatory site ligands as displacers of [³H]flumazenil binding in the rat CNS

Identification and immunohistochemical mapping of GABA_A receptor subtypes containing the δ-subunit in rat brain

[³H]-propyl β-carboline-3-carboxylate as a selective radioligand for the BZ₁ benzodiazepine receptor subclass