Mizokawa T, Kimura K, Ikoma Y, Hara K, Oshino N, Yamamoto T, Ueki S
Research Department, Nihon Schering K.K., Osaka, Japan.
Jpn J Pharmacol. 1988 Nov;48(3):357-64. doi: 10.1254/jjp.48.357.
In order to evaluate the potential usefulness of the drug as an antidepressant, acute and chronic effects of rolipram, a selective inhibitor of Ca2+- and calmodulin-independent cyclic AMP phosphodiesterase were investigated on muricide in olfactory bulbectomized (OB) rats. Upon single administration to OB rats, rolipram at a dosage of 1 mg/kg body weight suppressed the muricide for 2 hr after its administration. As a consequence of daily administration of rolipram, however, the incidence of muricide at 24 hr after the administration was decreased, and more than 60% of the rats did not exhibit the muricide on the 12th day. After the cessation of the administration, the incidence of the muricide returned to the initial level. The suppression of the muricide was not antagonized by several kinds of neurotransmitter blockers. Administrations of phosphodiesterase inhibitors and dibutyryl cyclic AMP as well as desipramine and clomipramine also suppressed the muricide dose-dependently. Repeated administration of desipramine also gave results similar to those of rolipram: repetition of a short suppression on the muricide was followed by the appearance of a long-lasting suppression. Differently from rolipram and desipramine, dibutyryl cyclic AMP did not cause long-lasting suppression, and even the direct effect (75% suppression) observed 30 min after its administration on the first day disappeared during its repeated administration for 14 days. From these results, rolipram was considered to show an antidepressant effect through the inhibition of Ca2+- and calmodulin-independent cyclic AMP phosphodiesterase.
为了评估该药物作为抗抑郁药的潜在效用，研究了选择性钙和钙调蛋白非依赖性环磷酸腺苷磷酸二酯酶抑制剂咯利普兰对嗅球切除（OB）大鼠杀鼠行为的急性和慢性影响。单次给OB大鼠注射1mg/kg体重的咯利普兰后，给药后2小时内杀鼠行为受到抑制。然而，由于每日给予咯利普兰，给药后24小时的杀鼠发生率降低，并且超过60%的大鼠在第12天未表现出杀鼠行为。给药停止后，杀鼠发生率恢复到初始水平。几种神经递质阻滞剂并未拮抗杀鼠行为的抑制作用。磷酸二酯酶抑制剂、二丁酰环磷腺苷以及地昔帕明和氯米帕明的给药也剂量依赖性地抑制了杀鼠行为。重复给予地昔帕明也得到了与咯利普兰相似的结果：对杀鼠行为的短暂抑制重复出现后，出现了持久的抑制。与咯利普兰和地昔帕明不同，二丁酰环磷腺苷并未引起持久的抑制，甚至在其首次给药后30分钟观察到的直接效应（75%抑制）在其14天的重复给药过程中也消失了。从这些结果来看，咯利普兰被认为是通过抑制钙和钙调蛋白非依赖性环磷酸腺苷磷酸二酯酶来发挥抗抑郁作用的。
