Pharmacological Analysis of GABAA Receptor and Sigma1R Chaperone Interaction: Research Report I?Investigation of the Anxiolytic, Anticonvulsant and Hypnotic Effects of Allosteric GABAA Receptors' Ligands

Two groups of facts have been established in previous drug development studies of the non-benzodiazepine anxiolytic fabomotizole. First, fabomotizole prevents stress-induced decrease in binding ability of the GABA(A) receptor's benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect. To prove our main hypothesis of Sigma1R involvement in GABA(A) receptor-dependent pharmacological effects, we performed a series of experiments on BALB/c and ICR mice using Sigma1R ligands to study anxiolytic effects of benzodiazepine tranquilizers diazepam (1 mg/kg i.p.) and phenazepam (0.1 mg/kg i.p.) in the elevated plus maze test, the anticonvulsant effects of diazepam (1 mg/kg i.p.) in the pentylenetetrazole-induced seizure model, and the hypnotic effects of pentobarbital (50 mg/kg i.p.). Sigma1R antagonists BD-1047 (1, 10, and 20 mg/kg i.p.), NE-100 (1 and 3 mg/kg i.p.), and Sigma1R agonist PRE-084 (1, 5, and 20 mg/kg i.p.) were used in the experiments. Sigma1R antagonists have been found to attenuate while Sigma1R agonists can enhance GABA(A)Rs-dependent pharmacological effects.

Automated summary

Previous drug development studies have established two groups of facts about the non-benzodiazepine anxiolytic fabomotizole. Firstly, it prevents the decrease in binding ability of the GABA(A) receptor's benzodiazepine site induced by stress. Secondly, it functions as a Sigma1R chaperone agonist, and its anxiolytic effect is blocked by Sigma1R antagonists. To investigate the involvement of Sigma1R in GABA(A) receptor-dependent pharmacological effects, various experiments were conducted on mice using Sigma1R ligands. The results show that Sigma1R antagonists attenuate while Sigma1R agonists enhance GABA(A) receptor-dependent pharmacological effects.