Neurophysiologic studies in animals have demonstrated interactions between different neurotransmitter systems and behavioral manifestations resulting from these interactions have been observed in clinical practice. Positron Emission Tomography (PET) has been applied to the assessment of neurotransmitter activity and to the measurement of interactions between neurotransmitter systems in the non-human primate and human brain at Brookhaven National Laboratory. The neurotransmitter interaction paradigm, derived from these basic neuroscience studies, will be applied to the measurement of neurotransmitter activity and interactions between neurotransmitter systems in normal human subjects. The eventual application of this work is to the study of interactions in schizophrenic patients. The rationale for the proposed studies is based on the characterization of mechanisms of pathophysiology and treatment resistance in schizophrenia. The interactions between dopamine and GABA, dopamine and acetylcholine and dopamine and serotonin were selected for study based upon the involvement of these systems in aspects of schizophrenic symptomatology and in the mechanism of action of alternative therapeutic strategies (e.g. GABA agonists, atypical neuroleptics). Towards this end, the first series of PET experiments will involve the measurement of alterations in dopamine receptor availability (using the radiotracer 11C-raclopride), after pharmacologic increase and decrease of dopamine activity. The interaction between dopamine-GABA will be measured by pharmacologically altering GABA activity and measuring the effects on dopamine receptor availability. A selective ligand for the serotonin receptor (18F-altanserin) will be characterized in the human, as has been done previously for the muscarinic cholinergic receptor (11C- benztropine). Finally, the interactions between dopamine-acetylcholine and dopamine-serotonin will be measured by pharmacologically altering dopamine activity and measuring effects on muscarinic cholinergic (11C- benztropine) and serotonergic (18F-altanserin) receptor availability. Rather than examining receptor number within an individual neurotransmitter system, this novel experimental approach represents an opportunity to study the dynamic interactions between systems. These studies will form the basis for the subsequent investigation of the pathophysiologic mechanisms underlying symptomatology in schizophrenia (e.g. negative symptoms, treatment resistance) and mechanisms of responsive or adaptive alterations secondary to treatment.
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