Neuropharmacological evidence for an interaction between the GABA uptake inhibitor Cl-966 and anxiolytic benzodiazepines

[1-[2-[bis(trifluoromethyl)-phenyl]methoxy]ethyl]-1,2,5,6- tetrahydro-3-pyridine-carboxylic acid, HCl (CI-966, Parke-Davis) is a new specific inhibitor to GABA uptake to neurons that is severalfold more potent than for inhibition of glycine or glutamate uptake. CI-966 crosses the blood-brain barrier and when injected intravenously into rats (doses up to 10.5 μM/kg = 5.0 mg/kg) produces only marginal behavioral effects. CI-966 also produces a modest reversal of punished-suppressed drinking behavior in thirsty rats both in the conflict and phenylenetetrazole (PTZ)-induced proconflict Vogel test. However an inactive dose of CI-966 (6.3 μM/kg i.v., 90 min prior to the test) significantly potentiated the anticonflict and anti-PTC-induced proconflict action of diazepam and alprazolam. The anticonflict/antiproconflict ED50 ratio for diazepam was shifted from 1.2 to 1.0 and that of alprazolam from 13.0 to 7.0 after pretreatment with CI-966. These results suggest that CI-966, while it may produce increasing GABAergic tone throughout the CNS, selectively enhances the action of GABA at GABA(A) receptor subtypes whose sensitivity is preferentially increased by administration of positive allosteric modulators. Therefore CI-966 may represent a very useful drug to study modifications of animal behavior in relation to the function of GABAergic transmission in specific brain areas.