Dysfunction of dopamine systems in the brain have been implicated in endocrine, neurological, and psychiatric disorders and dopaminergic drugs are widely prescribed for these disorders. Brain dopamine receptors are clearly implicated as the targets of these drugs. These receptors are in a mobile, dynamic state and can be modulated by drugs, lesions, diseases, hormones, and other challenges. For example, post-mortem brains of schizophrenia and Parkinson patients have altered levels of dopamine receptors, a consequence of dopamine drug therapies and/or the disease states. Although the end status of dopamine receptor modulation by drug treatment has been described, little is known about the mechanisms of drug-induced receptor adaptive processes. The continuation to develop fluorescent probes as a novel approach to study cellular and subcellular distribution of dopamine receptors and their regulation will occur during the Phase II of this research. Based on the information from the Phase I study, fluorescent derivatives of D1 and D2 selective agonist ligands with higher affinity and improved fluorescence characteristics will be prepared. The research will determine the affinity and selectivity of these compounds for dopamine receptors and test the retention of agonist properties. The most promising of these novel ligands will be evaluated on tissue sections by fluorescence microscopy, biotin-avidin coupling, and autoradiography. Experiments will be conducted on receptor mobility in response to agonist challenge on attainment of receptor-specific fluorescence.
