This is a competing renewal of studies of P50 sensory gating in schizophrenia. Clozapine improves impaired P50 auditory gating to a greater extent than any other antipsychotic. This improvement correlates with clinical improvement. Why clozapine is more effective than other atypicals is not clear, especially since P50 gating is mediated by the alpha-7 nicotinic receptor, not directly acted on by clozapine. Similar atypicals do not effectively improve impaired P50 gating. However, clozapine is a more effective 5HT3 antagonist than either olanzapine or quetiapine. 5HT3 blockade releases acetylcholine, which would stimulate .7 nicotinic receptors responsible for the mediation of P50 gating.
Our specific aims test this hypothesis in schizophrenic patients and in DBA/2 mice, which have impaired gating and deficits in alpha-7 nicotinic receptors. We will: 1) Determine whether adding ondansetron (a specific 5HT3 antagonist) acutety to schizophrenic patients taking olanzapine or quetiapine improves P50 gating; 2) Determine whether adding a daily dose of ondansetron will enhance P50 gating in patients stable on olanzapine or quetiapine; 3) Assess if improvement in cognitive deficits occurs with improvement in P50 gating; 4) Determine if blockade of 5HT3 receptors with ondansetron will improve gating in DBA/2, chronic-cocaine-treated C3H, and C3H congenic mice treated with quetiapine, olanzapine, or aripiprizole; and 5) Determine if adding tropisetron, a 5HT3 antagonist with documented .7 agonist activity, will produce greater improvement in gating in DBA/2, chronic-cocaine-treated C3H, and C3H congenic mice. Tropisetron is not yet available for human use In the United States, so this project will' assess whether it will be worthwhile to obtain an IND for testing in patients. A second hypothosis is that dopaminergic antagonism or downregulation must be added to prevent the 5HT3 antagonist-mediated release of catecholamines from interfering with the improvement due to the increased acetylcholine release. We will test adpiprazole, a partial agonist at the D2 and 5HT1A receptors, with ondansetron in human and animals to assess whether this combination will also improve auditory gating. Elucidating a potential mechanism by which clozapine alleviates a neurophysiological deficit may help us design better medications in the future.
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