Effect of zaleplon on learning and memory in rats

Although structurally not a benzodiazepine, 3'-(3-cyanopyrazolo [1,5-a] pyrimidin-7-yl)- N-ethylacetamide (zaleplon) it acts via the benzodiazepine site of the GABA(A) receptor. In the present study, we investigated the effects of zaleplon on learning and memory in rats in comparison with triazolam and nitrazepam. Oral administration of zaleplon and the reference drugs dose-dependently lessened the step-through latency in the test session of a passive avoidance task and increased the latency for reaching the hidden platform in the Morris water maze task, indicating the amnesic effect of the test drugs. The amnesic liability ratio for zaleplon in the passive avoidance task to sleep inducing activity was 19.6, for triazolam and nitrazepam 4.2 and 5.9, respectively. The liability ratios derived from the Morris water maze task for zaleplon, triazolam and nitrazepam were 10.2, 0.9 and 0.6, respectively. The results may indicate that zaleplon has a preferential sedative effect and that the sedative dose does not interfere with learning and memory. In a binding study, zaleplon displaced bound [(3)H]flunitrazepam from membrane preparations from the rat hippocampus with an IC(50) of 4,454.5 nM. In contrast, triazolam and nitrazepam displaced the binding of [(3)H]flunitrazepam to the membrane with IC(50) values of 15.5 nM and 83.6 nM, respectively. The efficacy of zaleplon for the competitive inhibition of [(3)H]flunitrazepam binding to the membrane preparation from hippocampus was thus less than that of triazolam and nitrazepam. These results suggest that zaleplon is characterized by a reduced amnesic liability, which may be due to its low affinity for the benzodiazepine site of the GABA(A) receptor in the hippocampus.