RECENT DEVELOPMENTS IN THE BEHAVIORAL PHARMACOLOGY OF BENZODIAZEPINE-(OMEGA) RECEPTORS - EVIDENCE FOR THE FUNCTIONAL-SIGNIFICANCE OF RECEPTOR SUBTYPES

Recent research in molecular biology has demonstrated the complexity o f GABA(A) receptors and shown that benzodiazepine (BZ-omega) receptor subtypes have a structural reality. It is therefore appropriate to ask whether the different pharmacological effects produced by benzodiazep ines (anticonvulsant activity, anxiety reduction, motor incoordination , learning deficits, characteristic discriminative stimulus effects, t olerance and dependence) are associated with activity at different rec eptor subtypes. The present paper reviews the literature dealing with the behavioral effects of novel BZ (omega) receptor ligands relevant t o the question of the functional significance of the BZ(1) (omega(1)) and BZ(2) (omega(2)) receptor subtypes. The only drugs currently avail able with a considerable degree of selectivity are alpidem and zolpide m. These compounds have relatively high affinity for GABA(A) receptors containing the alpha(1) subunit (corresponding to the BZ(1) (omega(1) ) subtype) and very low affinity for receptors with the alpha(5) subun it (corresponding to one type of BZ(2) (omega(2)) receptor). Pharmacol ogical effects observed with these, and other, less selective compound s 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 g iving rise to sedation or motor incoordination and BZ(1) (omega(1)) se lective drugs appear to disrupt memory only at sedative doses; (b) Sel ectivity for BZ(1) (omega(1)) receptors may be associated with sleep-i nducing activity but not with motor incoordination, suggesting that BZ (2) (omega(2)) receptors may be of particular importance in mechanisms of muscle relaxation; (c) The discriminative stimulus effects of diff erent BZ (omega) receptor ligands are not identical and differences ma y be related to receptor selectivity; (d) Compounds with BZ(1) (omega( 1)) selectivity and compounds with low intrinsic activity produce litt le or no tolerance and dependence. A wider range of selective compound s will be necessary to investigate these factors in detail and many di fferent pharmacological profiles can be expected from drugs with selec tivity and different levels of intrinsic activity.