Speaker: Professor Anthony Grace, University of Pittsburg
Date/Time: 13 October 2016, 4-6pm
Venue: Lecture Theatre, Hadyn Ellis Building, Cardiff University
Lecture Summary: Dopamine Neuron Regulation & its Implications for the Treatment and Prevention of Schizophrenia
Most drug treatments for schizophrenia target the dopaminergic system, but many gene variants linked to schizophrenia (and subsequently targeted for research) are relevant to NMDA receptors (NMDARs) in the hippocampus. In his lecture at Cardiff University’s Hadyn Ellis Building, Professor Anthony Grace sketched out an important pathway linking the NMDARs of the hippocampus and the dopaminergic system which may shed light on pharmaceutical trials of new schizophrenia drugs.
The hippocampus is important for creating context for environmental stimuli. When incoming stimuli is deemed irrelevant due to context, the hippocampus normally stimulates the release of GABA to suppress the responsive dopamine neurons. Hippocampal moderation of this system may be impacted by genetic variants of NMDARs. If the hippocampus fails to properly suppress the dopaminergic system because of this, dopaminergic responses cannot distinguish between salient and irrelevant environmental stimuli, leading to hyperawareness. A patient might start to confabulate reasons for this state, leading to the delusions characteristic of schizophrenia. No context is irrelevant, so the patient may feel constantly alert and threatened.
Current antipsychotic drugs target the dopamine system rather than the hippocampal NMDAR response upstream in this pathway. These dopamine targeted antipsychotics may interfere with new pharmacological tests targeting NMDARs. While typical clinical trials of new drugs take patients off of their current medication for seven days before test administration, Professor Grace anticipates this is not enough time to reset the patient’s dopamine system. When his lab introduced this pattern of medication and testing to their MAM model of schizophrenia* (a neurotoxin administered prenatally) , it interfered with the successful treatment effects they had previously observed using their NMDAR targeted drugs on naive schizophrenia animal models. These results suggested some failed clinical trials using drugs targeting NMDARs may warrant further investigation.
*the accuracy of any rodent model of schizophrenia is debatable, but useful for the purpose of this talk.
Du, Y., & Grace, A. A. (2016). Loss of parvalbumin in the hippocampus of MAM schizophrenia model rats is attenuated by peripubertal diazepam.International Journal of Neuropsychopharmacology, pyw065. https://www.ncbi.nlm.nih.gov/pubmed/27432008