Effects of rolipram on in vivo dopamine receptor binding

Summary. In order to clarify whether changes in brain concentrations of the second messenger cyclic AMP (cAMP) affect in vivo receptor binding in the brain, the effects of rolipram, a selective inhibitor of phosphodiesterase type 4 (PDE₄), on dopamine receptor binding in the mouse brain were studied. Rolipram significantly decreased in vivo ³H-SCH 23390 (dopamine D₁ selective radioligand) binding in the mouse striatum in a dose-dependent manner. In vivo saturation experiments together with the kinetic analysis of ³H-SCH 23390 binding revealed that the apparent association rate constant (k_on) for ³H-SCH 23390 binding rather than the maximum number of binding sites available (B_max) was decreased by rolipram. ³H-N-methylspiperone (NMSP, dopamine D₂ selective radioligand) binding in the mouse striatum was also decreased by rolipram whereas no significant changes in ³H-raclopride (dopamine D₂ selective radioligand) binding were observed. As ³H-raclopride binding has been reported to be much more sensitive than ³H-NMSP binding to competition by endogenous dopamine, the decreases in ³H-SCH 23390 and ³H-NMSP binding cannot be attributed to competitive inhibition by endogenous dopamine. These results indicate that changes in second messenger cAMP concentrations may affect the apparent bimolecular association rate constant (k_on) of dopamine receptor binding in intact brain. This may be mediated by changes in the receptor micro-environment and altered actual free ligand concentration surrounding the receptors. Received August 16, 2001; accepted November 13, 2001 Published online June 20, 2002