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The glutamate hypothesis is a new theory of schizophrenia which proposes that deficient glutamatergic transmission at the NMDA receptor underlies the positive, negative, and cognitive symptoms of the disorder. In addition to tracing the development of the glutamate hypothesis in depth, this senior project presents a study investigating the effects of a novel antipsychotic in zebrafish. Zebrafish are an emerging model of several CNS disorders, including schizophrenia, and it has been demonstrated that NMDA-R antagonism induces motor hyperactivity in zebrafish adults and larvae. Previous research supports an ability of typical and atypical antipsychotics to reverse these motor effects in zebrafish adults. The present study investigates the motor effects of MK-801 administration in TL zebrafish larvae (n = 208) at two dose levels, as well as the ability of CHPG (an agonist at the metabotropic glutamate 5 receptor) to reverse these effects. The findings indicate that MK-801 decreased motor activity at a dose of 20 mM. CHPG increased motor activity at a dose of 360 mM, an effect that was blocked by co-administration of 2 mM MK-801. The relevance of these findings to the development of antipsychotics based on the glutamate hypothesis is discussed.
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Vitale, William, "The Glutamate Hypothesis of Schizophrenia: Assessment of a Novel Antipsychotic in Zebrafish Larvae" (2012). Senior Projects Spring 2012. 376.