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

Psychopharmacology (Berl). 1999 Sep;146(2):205-13. doi: 10.1007/s002130051108.


Rationale: It has been suggested that different BZ (omega) 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 BZ(1) (omega(1)) receptor antagonist beta-CCT on the pharmacological effects of the selective BZ(1) (omega(1)) receptor agonist zolpidem and the non-selective BZ (omega) receptor agonist diazepam in behavioural, biochemical and electrophysiological experiments was assessed.

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 seizures produced by isoniazid, but beta-CCT failed to affect their action on seizures 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 diazepam. In tests designed to investigate the central depressant activity of drugs, beta-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 beta-CCT for BZ(1) (omega(1)) sites as indicated by the preferential displacement of [(3)H]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 cells expressing the alpha(1)beta(2)gamma(2) receptor or in cerebellar Purkinje 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.

Conclusion: These results are consistent with the hypothesis that BZ(1) (omega(1)) receptors play an important role in the anxiolytic and sedative/hypnotic effects of BZ (omega) receptor ligands, whereas activity at BZ(2) (omega(2)) sites might be associated primarily with muscle relaxation.

MeSH terms

  • Animals
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Anxiety Agents / pharmacology
  • Anticonvulsants / pharmacology
  • Behavior, Animal / drug effects*
  • Benzodiazepines / pharmacology*
  • Binding, Competitive / drug effects
  • Carbolines / pharmacology
  • Diazepam / pharmacokinetics
  • Diazepam / pharmacology
  • Flumazenil / pharmacokinetics
  • GABA Antagonists / pharmacology
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Hypnotics and Sedatives / pharmacokinetics
  • Hypnotics and Sedatives / pharmacology
  • Ligands
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Motor Activity / drug effects
  • Muscle Relaxants, Central / pharmacology
  • Patch-Clamp Techniques
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects*
  • Zolpidem


  • Anti-Anxiety Agents
  • Anticonvulsants
  • Carbolines
  • GABA Antagonists
  • GABA-A Receptor Agonists
  • GABA-A Receptor Antagonists
  • Hypnotics and Sedatives
  • Ligands
  • Muscle Relaxants, Central
  • Pyridines
  • Receptors, GABA-A
  • Benzodiazepines
  • Flumazenil
  • Zolpidem
  • tert-butyl beta-carboline-3-carboxylate
  • Diazepam