Date of Award
Sylvia A. Rabacchi, Ph.D
Edward G. Tall, Ph.D
Agela V. Klaus, Ph.D
schizophrenia, glutamate, animal models, drug efficacy, dopamine, psychosis
For many years the dominant theory surrounding the cause of schizophrenia was focused on elevated dopamine levels found in critical areas of the brain. Recently a new theory has emerged pointing to elevated glutamate levels resulting from hypofunction of NMDA receptors and hypoactivity of GABAergic neurons which normally inhibit glutamatergic cells in a tonic manner. Therefore, while traditional antipsychotics directly block dopamine receptors, some of the newly generated compounds are designed to modulate glutamate to normal levels.
I propose testing the efficacy of the metabotropic glutamate 5 receptor modulator LSN2463359, previously shown to act as an indirect agonist of the NMDA receptor, in two different animal models of schizophrenia. Our study found that when LSN2463359 was administered to rats given SDZ 220-581 (an NMDA antagonist) levels of GABA, glutamate, dopamine and NAA (a marker for cell health) were modulated to normal levels. Furthermore, when the compound was administered to neuregulin-1 knockout mice, behaviors related to anxiety and social activity were also modulated to normal levels. Developing novel therapies targeting a different pathway involved with psychosis may help reduce side effects and may be beneficial in relieving symptoms not currently well treated by traditional antipsychotics.
Freamon, Dierdre M., "Testing the efficacy of LSN2463359, a metabotropic glutamate 5 receptor positive allosteric modulator, in animal models of schizophrenia" (2015). Seton Hall University Dissertations and Theses (ETDs). 2130.