Increment of in vivo binding of [³H]SCH 23390, a dopamine D₁ receptor ligand, induced by cyclic AMP-dependent protein kinase in rat brain

The effects of cyclic AMP (cAMP)-related compounds on in vivo [³H]SCH 23390 binding to striatal dopamine D₁ receptors were investigated using autoradiography in order to clarify the possible regulation of the cAMP-dependent mechanisms in the in vivo ligand-receptor bindings in the living brain. Intrastriatal infusion of the cAMP analogue, N6,2′-O-dibutyryl-cyclic AMP (db-cAMP; 5, 25 and 100 nmol/side) produced a dose-dependent increase of in vivo [³H]SCH 23390 binding in conscious rats. This increasing effect of [³H]SCH 23390 binding completely disappeared by 6 h after the infusion of db-cAMP. A similar increase of in vivo [³H]SCH 23390 binding to striatal D₁ receptors was also observed by intrastriatal injection of 8-bromo-cyclic AMP (8Br-cAMP, 100 nmol/side). Pretreatment with Rp-cyclic AMP triethylamine (Rp-cAMPS, 100 nmol/side), an inhibitor of the cAMP-dependent protein kinase (PKA), completely blocked the increasing effect of [³H]SCH 23390 binding induced by db-cAMP. In contrast, in vitro [³H]SCH 23390 binding was not significantly altered by intrastriatal infusion of db-cAMP, which indicated that the maximum number of binding sites (B_max) for D₁ receptors was not changed. The kinetic analysis employed the graphical method indicated that a db-cAMP-induced increase of in vivo [³H]SCH 23390 binding was mainly due to an increase in the bimolecular association rate constant (k_on). These results strongly indicate that the PKA-mediated phosphorylation may play a pivotal role in the regulating the in vivo [³H]SCH 23390 dopamine D₁ receptor binding in intact rat brain.