Effect of chronic haloperidol, endogenous dopamine, and selective D¦1 competitors on in vivo D¦1 receptor binding in rat brain

grantor: University of Toronto'Rationale'. The dopamine (DA) D1 receptor (D1R) exists in two interconvertible high- (D1 HIGH) and low-affinity affinity states. Only agonists can differentiate them, antagonists cannot. The D1HIGH was altered in disease studies in which the total density was unchanged. Yet, endogenous DA may not reach the extrasynaptic D1R. 'Objectives'. The overall objective of this project is to utilize the D1 agonist R-[11C]SKF 82957 to assess D1R changes in humans using PET, and in animal models. 'Methods'. Binding of R-[ 11C]SKF 82957 and [11C]SCH 23390 was assessed in rats following chronic 21-day haloperidol treatment; acute manipulation of endogenous DA with cocaine, amphetamine, and GBR 12909; and acute administration of direct D1R ligands SCH 23390, SKF 38393, SKF 81297, and SKF 82958. 'Results'. Radioligand uptake was greatest in D 1-rich striatum and olfactory tubercles. Neither haloperidol nor increased DA altered radiotracer binding. Direct D1R ligands significantly decreased the binding of both radioligands in D1-rich regions, in correlation with binding affinity for the D1HIGH. ' Conclusions'. The binding of R-[11C]SKF 82957 or [ 11C]SCH 23390 was not affected by haloperidol or DA, but was significantly decreased by direct D1R ligands based on affinity for the D 1HIGH.M.Sc