Rolipram and Its Optical Isomers, Phosphodiesterase 4 Inhibitors, Attenuated the Scopolamine-Induced Impairments of Learning and Memory in Rats

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Abstract
We investigated the effects of (±)-rolipram, a phosphodiesterase (PDE) 4 inhibitor, and its isomers on scopolamine-induced deficits of learning and memory in rats using an 8-arm radial maze task and a passive avoidance task. 1) In the 8-arm radial maze task, (±)-rolipram (0.02-0.2 mg/kg, p.o.), (-)-rolipram (0.01-0.02 and 0.2-0.5 mg/kg, p.o.) and (+)-rolipram (20-50 mg/kg, p.o.) attenuated the scopolamine-induced deficits of spatial cognition. As for the minimum effective dose of each drug, (-)rolipram was 2 and 2000 times as potent as (±)-rolipram and (+)-rolipram, respectively. (-)-Rolipram produced a biphasic dose-response and (±)-rolipram produced a broad dose-response. 2) (±)-Rolipram and its isomers also attenuated the scopolamine-induced deficits in the passive avoidance response. Also for the minimum effective dose, (-)-rolipram (0.01 0.02 mg/kg) was 2 and 200 times as potent as (±)rolipram (0.02-0.1 mg/kg) and (+)-rolipram (2 mg/kg). 3) The behaviorally effective doses of (±)rolipram and its isomers also enhanced the oxotremorine-induced tremors in mice. Comparing these racemic isomers, (-) and (±)-rolipram have more potent effects than (+)-rolipram on scopolamine-induced deficits in the 8-arm radial maze task and passive avoidance task. Especially (±)-rolipram has a wide dose range in these behavioral study. These results suggest that the ameliorating effects of rolipram might result from the indirect potentiation of various transmitters including cholinergic and noradrenergic systems by an increase in cAMP with the inhibition of PDE4.