ENDOGENOUS DOPAMINE LIMITS THE BINDING OF ANTIPSYCHOTIC-DRUGS TO D-3 RECEPTORS IN THE RAT-BRAIN - A QUANTITATIVE AUTORADIOGRAPHIC STUDY

[H-3]7-hydroxy-N,N-di-n-propyl-2-aminotetralin was used as a radioliga nd for the autoradiographic measurements of dopamine D-3 receptors in rat and human brain. Preincubation of the brain sections was necessary to obtain binding of the radioligand in the islands of Calleja and in the nucleus accumbens, but not in cerebellar lobules 9/10 of the rat. D-3 receptors were also totally occluded in unwashed sections of the human striatum. The radioligand binding to D-3 receptors was maximal a fter preincubating the sections for at least 10 min. Pretreatment of t he animals with reserpine or tetrabenazine, which results in a severe depletion of endogeneous monoamines, strongly reduces the occlusion of D-3 receptors in unwashed brain sections. The occlusion of dopamine D -3 receptors in brain sections suggests that the in vivo access to D-3 receptors may be locally inhibited by endogenous dopamine. The in vit ro binding affinities of 12 antipsychotic drugs for D-2 and D-3 recept ors were evaluated in competition binding experiments, using both rat and cloned human receptors. Most of the compounds showed only a slight ly lower affinity for D-3 than for D-2 receptors in vitro. Affinities of the antipsychotic drugs for cloned human D-2L and D-3 receptors wer e very close to their affinities for the rat receptors. In vivo occupa ncy of these receptors in the rat brain was measured ex vivo by quanti tative autoradiography, 2 hours after subcutaneous drug administration . For most compounds, occupancy of D-3 receptors, as compared to D-2 r eceptor occupancy, was lower than expected from the corresponding in v ivo affinity ratios. For the new antipsychotic risperidone, in vine oc cupancy of D-3 receptors was measured both in the islands of Calleja a nd in the cerebellar lobules 9/10. This compound was three times less potent for the occupancy of D-3 receptors in the islands of Calleja th an in the cerebellum, an area lacking endogenous dopamine (ED(50) = 28 and 10 mg kg(-1), respectively). Based on the observations in the rat brain, it may reasonably be supposed that therapeutic dosages of anti psychotic drugs will induce in patients only a minor occupancy of D-3 receptors in brain areas containing high dopamine concentrations. The role of dopamine D-3 receptors as a target of antipsychotic drugs may therefore be less important than previously thought.