PHARMACOLOGY OF NICOTINIC RECEPTORS

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This project will replicate and extend the relationship of genetic polymorphisms in CHRNA 7 to the phenotype of inhibitory dysfunction as measured by inhibition of the P50 response to repeated auditory stimuli in schizophrenic and control subjects. Alpha7-specific agonists will be tested in schizophrenics to determine if they normalize P50 response and to what extent they also affect the neurocognitive features and clinical symptoms of schizophrenia. We have received FDA approval for the administration of 3-2,4 dimethoxybenzylidene anabaseine to humans and in an initial experiment demonstrated that the drug improves deficient P50 inhibition. The alpha7 nicotinic receptor not only has a role in neurotransmission, which we demonstrate by P50 inhibition, but it also has a major developmental role that we have characterized by observing differences in the regional distribution of hippocampal interneurons in animal models with acra7 variants. Because correction of neurotransmission deficits related to alpha7 receptors does not address this developmental role, we will also employ mouse animal models to determine if alpha7 agonist treatment in the perinatal period affects the development of interneurons. To extend the hippocampal pathophysiology we have postulated to include the deficits in learning and memory found in schizophrenia, we now show deficits in learning in mice with the acra7 (murine CHRNA 7) null mutation, as well as evidence in humans that P50 abnormalities correlate with decreased declarative memory. We present new data that perinatal choline supplementation to mice with acra7 polymorphisms results in offspring with normal inhibition of the hippocampal response to repeated sounds. In conjunction with Project by Restrepo, we will measure olfactory function in schizophrenics. For Project by Ross, we will record P50 inhibition as a basic measure of inhibitory function to be related to their measurements in children and adults.