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

Abstract 

Rationale: It has been suggested that different BZ (ω) receptor subtypes may mediate distinct behavioural effects of BZ receptor ligands. Objective: The present study examined this hypothesis further. Methods: The antagonism exerted by the selective BZ₁ (ω₁) receptor antagonist β-CCT on the pharmacological effects of the selective BZ₁ (ω₁) receptor agonist zolpidem and the non-selective BZ (ω) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed. Results:β-CCT which was devoid of activity per se, antagonized the effects of the non-selective BZ (ω) receptor full agonist diazepam and the selective BZ₁ (ω₁) receptor full agonist zolpidem against seizures produced by isoniazid, but β-CCT failed to affect their action on seizures produced by pentylenetetrazole (PTZ), suggesting that BZ₂ (ω₂) receptors may be primarily involved in the convulsant action of PTZ. In the light/dark test, β-CCT abolished the anxiolytic-like action of diazepam. In tests designed to investigate the central depressant activity of drugs, β-CCT antagonized the sedative effects of diazepam and zolpidem, but failed to modify clearly the myorelaxant effects of diazepam. These differences may be related to the selectivity of β-CCT for BZ₁ (ω₁) sites as indicated by the preferential displacement of [³H]flumazenil in BZ₁ (ω₁)-enriched structures as compared to BZ₂ (ω₂)-enriched structures in the mouse. In in vitro experiments, β-CCT antagonized the potentiation of the GABA-induced Cl^– current produced by zolpidem in HEK cells expressing the α₁β₂γ₂ receptor or in cerebellar Purkinje neurones, while it failed to modify the diazepam potentiation at either α₃β₂γ₂ or α₅β₃γ₂ receptor subtypes. Conclusion: These results are consistent with the hypothesis that BZ₁ (ω₁) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (ω) receptor ligands, whereas activity at BZ₂ (ω₂) sites might be associated primarily with muscle relaxation.