Effects of dopamine on the in vivo binding of dopamine D-2 receptor radioligands in rat striatum

The effects of moderate changes in extracellular dopamine concentrations on the in vivo binding of specific dopaminergic D-2 radioligands with differe nt affinities and kinetics were investigated in rats. Either [I-125]NCQ298 (Kd = 19 pM), or [I-125]iodolisuride (Kd = 0.27 nM) or [H-3]raclopride (Kd = 1.5 nM) were administered intravenously (IV) to animals 1 h after the int raperitoneal (IP) injection of either alpha-methyl-p-tyrosine (AMPT) (250 m g/kg) or nomifensine (15 mg/kg), or saline. The kinetics of radioactivity c oncentration in the striatum, cerebellum, and plasma were measured for up t o 4 h after [I-125]NCQ298 or [I-125]iodolisuride injection and up to 1.5 h after [H-3]raclopride injection. For each tracer, the striatum-to- cerebell um radioactivity concentration ratios (S/C) and the binding potential (BP), calculated as the association to dissociation binding rate constant ratios (k3/k4), were assessed and related to the changes in extracellular dopamin e concentration induced by drug treatments. Results show that S/C and BP of [H-3]raclopride were significantly diminished by pretreatment with nomifen sine, a drug that increases extracellular dopamine concentration. Nomifensi ne pretreatment induced no changes in the in vivo binding indexes of the hi gh affinity [I-125]NCQ298 and a slight but not significant decrease of the binding indexes of [I-125]iodolisuride. Treatment with AMPT, which induced a 40% reduction in dopamine concentration, did not change [I-125]NCQ298 bin ding indexes but slightly increased those of [H-3]raclopride and [I-125]iod olisuride. In conclusion, the change of dopamine concentration induces modi fication of radiotracer kinetics. Thus, the combined use of tracers with hi gh and low affinities could allow us to obtain information both on receptor density and neurotransmitter release in vivo. However, as indicated by the [H-3]raclopride study with AMPT, small changes in the concentration of int rasynaptic dopamine cannot be easily detected. NUCL MED BIOL 26;1:91-98, 19 99. (C) 1998 Elsevier Science Inc.