Takashi Egawa (#), Kenichi Mishima, Yoshiaki Matsumoto, Kiyo Iwasaki,
Katsunori Iwasaki and Michihiro Fujiwara (*)
Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences,
Fukuoka University, Fukuoka 814-80, Japan
(#) Present address: Department of Hospital Pharmacy, Yame General Hospital,
Fukuoka 834,Japan
(*) To whom correspondence should be addressed.
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 - 0.02mg/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.
Keywords: Rolipram, Radial arm maze, Passive avoidance, Tremor, Scopolamine