Endogenous dopamine limits the binding of antipsychotic drugs to D₃ receptors in the rat brain: a quantitative autoradiographic study

Summary

[³H]7-hydroxy-N,N-di-n-propyl-2-aminotetralin was used as a radioligand for the autoradiographic measurements of dopamine D₃ 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. D₃ receptors were also totally occluded in unwashed sections of the human striatum. The radioligand binding to D₃ receptors was maximal after preincubating the sections for at least 10 min. Pretreatment of the animals with reserpine or tetrabenazine, which results in a severe depletion of endogeneous monoamines, strongly reduces the occlusion of D₃ receptors in unwashed brain sections. The occlusion of dopamine D₃ receptors in brain sections suggests that thein vivo access to D₃ receptors may be locally inhibited by endogenous dopamine.

Thein vitro binding affinities of 12 antipsychotic drugs for D₂ and D₃ receptors were evaluated in competition binding experiments, using both rat and cloned human receptors. Most of the compounds showed only a slightly lower affinity for D₃ than for D₂ receptorsin vitro. Affinities of the antipsychotic drugs for cloned human D_2L and D₃ receptors were very close to their affinities for the rat receptors.In vivo occupancy of these receptors in the rat brain was measuredex vivo by quantitative autoradiography, 2 hours after subcutaneous drug administration. For most compounds, occupancy of D₃ receptors, as compared to D₂ receptor occupancy, was lower than expected from the correspondingin vivo affinity ratios. For the new antipsychotic risperidone,in vivo occupancy of D₃ receptors was measured both in the islands of Calleja and in the cerebellar lobules 9/10. This compound was three times less potent for the occupancy of D₃ receptors in the islands of Calleja than in the cerebellum, an area lacking endogenous dopamine (ED₅₀=28 and 10 mg kg⁻¹, respectively).

Based on the observations in the rat brain, it may reasonably be supposed that therapeutic dosages of antipsychotic drugs will induce in patients only a minor occupancy of D₃ receptors in brain areas containing high dopamine concentrations. The role of dopamine D₃ receptors as a target of antipsychotic drugs may therefore be less important than previously thought.