Schizophrenia is thought to result from the altered development of functionally inter-related forebrain structures that mediate goal-directed behavior and cognition. It has been proposed that a primary pathology in these forebrain structures results in a profound disruption of dopaminergic function that can manifest as positive or negative symptoms of schizophrenia. According to this hypothesis, negative symptoms result from diminished dopaminergic function, while positive symptoms are manifested during bouts of abnormally augmented dopaminergic function. The observation that non-competitive antagonists of the N-methyI-D-aspartate (NMDA) type of glutamate receptor (such as phencyclidine) can result in symptoms in normal individuals that are indistinguishable from schizophrenic patients suggests that glutamatergic hypofunction may play a role in the forebrain pathology that leads to dopaminergic dysregulation. In order to study the cellular mechanisms mediating interactions between these glutamatergic forebrain pathways and dopaminergic pathways, a novel rat brain explant preparation has been developed. This preparation contains key regions of the forebrain potentially implicated in schizophrenia as well as dopaminergic midbrain neurons which send fibers into their normal forebrain targets in the striatum and cortex. The goal of this proposal is to utilize this preparation to test the hypothesis that chronic non-competitive NMDA receptor antagonist exposure (mimicking glutamatergic hypofunction) leads to augmented phasic dopaminergic responses in the ventral striatum. The following specific aims will be addressed: (1) Determine the effects of synaptically released dopamine on intrinsic properties of ventral striatal spiny neurons that are known to be altered by exogenously applied dopamine. (2) Determine the effects of synaptically released dopamine on evoked glutamatergic synaptic responses in spiny neurons that are known to be altered by exogenously applied dopamine. (3) Determine whether phasic (burst-evoked) actions of dopamine on intrinsic and synaptic properties of ventral striatal spiny neurons are altered by chronic phencyclidine exposure. These experiments may lead to insights into the cellular mechanisms of action of phencyclidine, and thus indirectly into mechanisms mediating schizophrenic symptoms in patients. This would provide important data useful for the development of more effective antipsychotic medications.
| Kadiu, I; Glanzer, J G; Kipnis, J et al. (2005) Mononuclear phagocytes in the pathogenesis of neurodegenerative diseases. Neurotox Res 8:25-50 |
