The D3 dopamine receptor is a novel receptor which has been implicated as a potential therapeutic target in the treatment of schizophrenia.This proposal addresses the issue of whether the D3 receptor mediates any of the therapeutic and/or side-effects of antipsychotic drugs. The hypothesis is that D3 receptors in limbic brain regions may mediate the therapeutic effects of antipsychotic drugs, while cerebellar D3 receptors may mediate certain neurological side-effects. Molecular, biochemical, pharmacological, anatomical, and behavioral approaches will be used to address the specific aims: (1) to determine how D3 receptors are regulated by tonic dopaminergic activity. The effects of unilateral and bilateral 6-OHDA lesions of the major dopamine projections on the density of D3 receptors and mRNA indiscrete brain regions will be examined using receptor autoradiography, receptor binding, and in situ hybridization. (2) to determine how D3 receptors are regulated by dopamine agonists and antagonists using receptor autoradiography, receptor binding, and in situ hybridization. (3) to determine D3 receptor occupation by antipsychotic drugs in vivo using receptor autoradiography. (4) to determine the effects of D3 receptor stimulation or blockade on neuronal activity in specific brain regions by assessment of (a) Fos expression and (b) cerebral glucose utilization. (5) to determine whether cerebellar D3 receptors have dopaminergic innervation and, if so, the source. Autoradiographic methods, measurement of catecholamines by HPLC-EC, and retrograde tracers will be used. (6) to determine whether cerebellar dopamine receptors are present in humans and other mammalian species using receptor autoradiography and in situ hybridization. (7) to determine the behavioral effects of microinjection of dopamine agonists and antagonists into cerebellar lobule 10. These studies will provide significant information regarding the functional role of D3 receptor, its potential involvement in the effects of antipsychotic drugs, and its suitability as a therapeutic target.
