Schizophrenia likely involves multiple pathophysiological elements, most of which are not affected by current neuroleptic treatments. The goal of this study is to investigate effects of a new drug therapy directed to one of these elements, a recently identified, genetically transmitted deficit in the a7 nicotinic acetylcholine receptor locus. The cx7 nicotinic receptor is a good candidate for the development of new therapeutic strategies for several reasons: (1) this receptor is the only currently identified neurotransmitter receptor for which there is independent biological and genetic evidence of involvement in the pathophysiology of schizophrenia; and (2) the pathophysiological dysfunction is closely associated with disordered attentional function, which has been found to be related to poor psychosocial outcome. The proposed experiments will identify the neurophysiological, neuropsychological, and clinical effects of a7 receptor activation in both schizophrenics and their relatives. Scientific questions about the role of the receptor in the pathophysiology of schizophrenia, as well as the issue of its utility as a therapeutic target, cannot be adequately addressed without the development of strategies for selective activation of the a7 receptor in human subjects. Therefore, included in the experimental plan are Phase 1, proof of principle, tests for a new a7 nicotinic agonist, 3-(2,4 dimethoxybenzylidene) anabaseine (DMXB-A).
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