Team Dopamine Project Goals

The foci of this collaborative research will include:

• Based on existing structural leads, develop novel drugs having high affinity and selectivity for D3 and/or D4 receptors, and characterize the receptor interactions and functional effects of these drugs in molecular expression systems and rat brain.
• Characterize novel Di-like ligands for utility as antiparkinsonian and potential antischizophrenic drugs.
• Focusing on the D2 molecular isoform, determine the mechanisms for, and implications of the isoform functional selectivity seen with tetrahydrobenzo[a]phenanthridines and other compounds. This will involve in vitro and in vivo studies using mammalian preparations, and later, examining these drugs in systems expressing only one molecular form of this class of receptors.
• Establish reliable in vitro mesencephalic dopaminergic neuronal preparations for single cell electrophysiology, and characterize drug effects in acutely dissociated striatal, nigral, and nucleus accumbens neurons. Compare with cultured cells expressing cloned D2, D3, and D4 receptors
• Model "D2-like" dopamine and muscarinic cholinergic receptors and determine structural elements that affect ligand binding, and conformation changes that determine the nature of interactions with different G-proteins.
• Develop and study models of neurotoxic insult to dopamine systems to understand the adaptive responses to neural injury at both the functional and molecular levels. These models would include partial striatal dopaminergic lesions, serving as a model of early Parkinson's disease to study disease effects on dopamine uptake and release. Other aspects of this work would compare dopamine release in anesthetized (previous work) and freely moving animals with an emphasis on effects on dopamine transporters and presynaptic inhibitory D2 receptors, and would also determine how key mechanisms (e.g., D1/D2 receptor interactions) are changed in such models. These data will be important in understanding and developing new therapies for Parkinson's disease and schizophrenia.
• To compare and contrast the effects on dopaminergic transmission of chronic administration of clozapine, an atypical neuroleptic agent, with haloperidol, a more traditional neuroleptic. These studies will search for possible differences in effects on the extrapyramidal system (caudate nucleus) and the limbic system (amygdala).
• Carry out preliminary development on several "orphan drug" projects in which promising data is available (e.g., for drugs affecting muscarinic, sigma, and serotonin systems). These projects should be advanced to see if novel or therapeutically promising compounds may result.

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