Rolipram, a stereospecific inhibitor of calmodulin-independent phosphodiesterase, causes?-adrenoceptor subsensitivity in rat cerebral cortex

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Abstract
Prolonged pretreatment of rats with the atypical antidepressant rolipram attenuates noradrenaline (NA) sensitivity of the cerebral cortical cAMP generating system. The development of this down-regulation is time (7 d treatment required) and dose dependent (EC50=0.35 mg/kg). Density ofβ-adrenoceptor as measured by (−)-3H-dihydroalprenolol [(−)-3H-DHA] binding is also reduced by rolipram pretreatment. The effect of rolipram is absolutely stereospecific for the (−)-enantiomer (ED50=0.18 mg/kg). In addition, only with this isomer, a reduction in daily weight gain was found compared to sham treated controls. Presynaptic denervation using intracerebroventricular (i.c.v.) injections of 6-hydroxydopamine (6-OHDA) prior to or during rolipram treatment did not completely block the effect of a rolipram treatment on down-regulation of cerebral corticalβ-adrenoceptors. The data favor a prea- and postsynaptic action of rolipram different from all other antidepressants studied so far in this experimental setting. Rolipram is known as inhibitor of brain phosphodiesterase. Using partially purified calmodulin-independent phosphodiesterase from brain it is shown that exclusively the (−)-enantiomer of rolipram inhibits phosphodiesterase with an IC50 of 1.25 μmol/l whereas the (+)-isomer possesses little potency. Since a marked stereospecificity for the (−)-isomer of rolipram was displayed in all pharmacological parameters tested so far with (+)- and (−)-rolipram, it is suggested that stereospecific and isozyme specific inhibition of cAMP-phosphodiesterase is, at least in part, related to the mechanism of action of the potential antidepressant drug rolipram and possibly of other antidepressants as well.

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