New evidence that the pharmacological effects of benzodiazepine receptor ligands can be associated with activities at different BZ (omega) receptor subtypes

Rationale: It has been suggested that different BZ (omega) receptor subtype s may mediate distinct behavioural effects of BZ receptor ligands. Objectiv e: The present study examined this hypothesis further. Methods: The antagon ism exerted by the selective BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor a gonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assess ed. Results: beta-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (omega) receptor full agonist diazepam and the selective BZ(1) (omega(1)) receptor full agonist zolpidem against seizu res produced by isoniazid, but beta-CCT failed to affect their action on se izures produced by pentylenetetrazole (PTZ), suggesting that BZ(2) (omega(2 )) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, beta-CCT abolished the anxiolytic-like action of diaze pam. In tests designed to investigate the central depressant activity of dr ugs, beta-CCT antagonized the sedative effects of diazepam and zolpidem, bu t failed to modify clearly the myorelaxant effects of diazepam. These diffe rences may be related to the selectivity of beta-CCT for BZ(1) (omega(1)) s ites as indicated by the preferential displacement of [H-3]flumazenil in BZ (1) (omega(1))-enriched structures as compared to BZ(2) (omega(2))-enriched structures in the mouse. In in vitro experiments, beta-CCT antagonized the potentiation of the GABA-induced Cl- current produced by zolpidem in HEK c ells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purki nje neurones, while it failed to modify the diazepam potentiation at either alpha(3)beta(2)gamma(2) or alpha(5)beta(3)gamma(2) receptor subtypes. Conc lusion: These results are consistent with the hypothesis that BZ(1) (omega) receptors play an important role in the anxiolytic and sedative/hypnotic e ffects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.