Project Summary

John Neumaier, M.D., Ph.D. (Independent Investigator 2003) of University of Washington, notes that 5-HT6 serotonin receptors are recently discovered G protein coupled receptors with a high affinity for several atypical antipsychotics (e.g., clozapine and olanzapine). These receptors may play a unique role in the action of these drugs—the enhancement of cognitive function, whereas schizophrenia is associated with broadly based cognitive impairment. Dr. Neumaier hypothesizes that 5-HT6 receptors in striatum (a part of the brain involved in goal directed behaviors and learning) may account for the cognitive enhancing features of several atypical antipsychotics. Using gene transfer techniques, he will overexpress the 5-HT6 receptor in a part of the striatum called the nucleus accumbens, thereby developing a way to overstimulate the 5-HT6 receptor system in the striatum selectively. He will study the resulting changes in the release of acetylcholine, a neurotransmitter involved in learning and cognition using brain tissue slices in vitro. He will investigate the effects of increased 5-HT6 expression in the striatum on cognition using a behavioral procedure that tests an animal’s ability to learn a task rewarded by food (Autoshaping). He believes 5-HT6 overexpression will impair learning and that 5-HT6 antagonists will reverse this. He hopes to establish a new model of cognitive enhancement mediated by 5-HT6 receptors to understand the mechanisms of atypical antipsychotic action.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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