Differential effects of benzodiazepine receptor agonists on hippocampal long-term potentiation and spatial learning in the Morris water maze.

The amnesic effect of benzodiazepine drugs has been well documented, though the mechanisms mediating this effect are unknown. Long-term potentiation (LTP) has been proposed as a mechanism by which information is stored in the mammalian central nervous system. This experiment sought to determine if benzodiazepines impair mnemonic processes by blocking LTP. Rats implanted with a stimulating electrode in the perforant path and a recording electrode in the dentate gyrus were given high-frequency stimulation after the administration of either chlordiazepoxide (5 mg/kg), diazepam (5 mg/kg) or CL 218,872 (10 mg/kg). None of these drugs completely blocked the induction of LTP as measured by changes in the magnitude of the population spike amplitude, though CL 218,872 significantly suppressed potentiation over the duration of recording (24 h). Moreover, the potentiation observed in diazepam-treated rats returned to baseline after 24 h. Two weeks after the last recording, the same implanted rats were given their previous drug and dose and then tested for spatial learning ability in the Morris water maze. Each drug resulted in a severe impairment of spatial learning, but had no effect on cue learning. Two days later, in the absence of drugs, the same rats readily acquired a reversed platform location. Together these results suggest that CL 218,872 may impair spatial learning by suppressing LTP in the perforant path but that chlordiazepoxide and diazepam can impair spatial learning in the absence of LTP suppression in this pathway.