Sensitivity of binding of high-affinity dopamine receptor radioligands to increased synaptic dopamine

PET and SPECT studies have documented that D2 radioligands of moderate affi nity? but not radioligands of high affinity, are sensitive to pharmacologic al challenges that alter synaptic dopamine levels. The objective of this wo rk was to determine whether the brain kinetics of high-affinity radioligand s for dopamine D1 ([H-3]SCH 23390) and D2 ([I-123]epidepride) receptors wer e altered by a prolonged elevation of synaptic dopamine induced by the pote nt cocaine analog RTI-55. Mice were injected intravenously with radioligand s either 30 min after or 4 h before intraperitoneal administration of RTI-5 5 (2 mg/kg). In separate experiments, the pharmacological effects of RTI-55 were assessed biochemically by measuring uptake of dopamine in synaptosome s prepared from RTI-treated mice and behaviorally by monitoring locomotor a ctivity. Consistent with the expected elevation of synaptic dopamine, RTI-5 5 induced a long-lasting decrement in dopamine uptake measured ex vivo, and a prolonged increase in locomotor activity. RTI-55 injected prior to the r adioligands induced a significant(P < 0.05) increase in striatal concentrat ion of [I-123]epidepride at 15 min, relative to saline-treated controls, bu t there were no differences between the two groups at later time-points. Fo r [H-3]SCH 23390, both initial striatal uptake and subsequent clearance wer e slightly increased by preadministration of RTI-55. Administration of RTI- 55 4 h after the radioligands (i.e., when it was presumed that a state of n ear equilibrium binding of the radioligands had been reached), was associat ed with a significant reduction of striatal radioactivity for both radiotra cers. Our results are consistent with increased competition between dopamin e and radioligand for binding to both D1 and D2 receptors after treatment w ith RTI-55. We suggest that the magnitude of the competition is reduced by failure of the receptor binding of high-affinity radioligands to rapidly at tain equilibrium. (C) 2000 Wiley-Liss, Inc.