Interactions between chemically different neurotransmitter systems provide the mechanisms responsible for maintaining homeostatic balance and for appropriate responses within the central nervous system (CNS) to changes in both the internal and external environment. The purpose of this proposal is to use positron emission tomography (PET) as a tool for further characterizing neurotransmitter interactions within the extrapyramidal motor system Specifically, we will examine interactions between the cholinergic, dopaminergic, GABAergic, and serotonergic systems in order to more completely understand the consequences of how a drug-induced perturbation in one of these neurotransmitter systems can manifest itself through any other neuroanatomically and/or functionally-linked system. Specific deficits in any one of these neurotransmitters have been implicated in abnormalities in motor coordination and psychiatric disorders. While PET studies have examined each one of these systems separately, studies designed to examine interactions between these neurotransmitters will provide a more complete understanding of the mechanisms responsible for these disorders. Previously we synthesized and measured the binding characteristics of a dopaminergic and cholinergic ligand and demonstrated that interactions between acetylcholine and dopamine can be measured with PET (Dewey, et al., 1991). The studies in this proposal will further our understanding of the role that GABA and serotonin play in these interactions. Pharmacologic intervention with drugs of known receptor specificity will be used in conjunction with the appropriate radiotracer to measure these effects. This unique strategy for studying neurotransmitter interactions in vivo has widespread clinical applications and may lead to a more complete understanding of many CNS disorders that have classically been attributed to a single neurotransmitter system (ie. schizophrenia, affective disorders, Parkinson's disease, Huntington's chorea, etc.). Furthermore, this approach takes full advantage of the unique capabilities of PET and the selective radiotracers 11C-benztropine (cholinergic), 11C-raclopride (dopamine D2), and 18F-altanserin (serotonergic, 5-HT2) for assessing dynamic neurotransmitter relationships and the consequences of their interactions-in the living brain. These studies will serve as the impetus for future investigations that will provide insight into the adaptive or responsive changes that occur in one neurotransmitter system following alterations in another. Finally, these studies can be used to assess the ability of a specific neurotransmitter system to adapt to drug-induced or pathological changes in the internal environment.
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