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

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 BZ 1 ( ω 1) and BZ 2 ( ω 2) 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 α 1 subunit (corresponding to the BZ 1 ( ω 1) subtype) and very low affinity for receptors with the α 5 subunit (corresponding to one type of BZ 2 ( ω 2) 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 BZ 1 ( ω 1) selective drugs appear to disrupt memory only at sedative doses; (b) Selectivity for BZ 1 ( ω 1) receptors may be associated with sleep-inducing activity but not with motor incoordination, suggesting that BZ 2 ( ω 2) 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 BZ 1 ( ω 1) 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.