This R01 proposal includes 3 major aims and experiments, which all focus on increasing the current understanding of glucose- and insulin-induced improvements in memory performance in aging patients with schizophrenia and healthy control adults. Schizophrenia is characterized by cognitive impairments for which there are no specific treatments, including a prominent impairment in memory performance. A series of investigations have found that raising circulating glucose levels can improve memory performance in animals, younger and older healthy humans, patients with Demential of the Alzheimer's type and patients with schizophrenia. Elevations of plasma insulin level alone, using a novel hyperinsulinemic-euglycemic """"""""clamp"""""""" technique, can also increase memory performance, suggesting the importance of insulin-induced increases in intracellular glucose availability. Experiment 1 aims to define the dose-response relationship of glucose to memory performance in patients with schizophrenia (and controls) across a wide age range, using multiple fixed oral glucose doses. Experiment 2 aims to define the dose-response relationship of insulin to memory performance in patients with schizophrenia (and controls) across a wide age range, using a hyperinsulinemic-euglycemic """"""""clamp"""""""" technique to measure performance across multiple fixed insulin doses during basal euglycemia. Based on preclinical evidence for insulin stimulation of NMDA glutamate receptor function, Experiment 3 aims to use a cognitively """"""""optimal"""""""" dose of insulin to provide evidence in humans for insulin remediation of NMDA receptor antagonist-induced memory impairment. The NMDA receptor antagonist, ketamine, is used to produce a state-of-the-art neurochemical model of schizophrenia, including an impairment of memory performance. Confirmation of an insulin effect to reverse ketamine-induced memory impairment would provide the first clinical evidence for a rational strategy to reverse memory impairment associated with NMDA receptor hypofunction in schizophrenia. The definition of dose-response relationships in Experiments 1 and 2 represents critical missing knowledge about the cognitive effects of the brain's primary energy substrate, glucose, and its fundamental regulator of intracellular availability, insulin. This knowledge is required to identify """"""""optimal"""""""" doses of insulin needed to further study therapeutic manipulations of brain glucose availability.
| Newcomer, J W; Craft, S; Fucetola, R et al. (1999) Glucose-induced increase in memory performance in patients with schizophrenia. Schizophr Bull 25:321-35 |
| Fucetola, R; Newcomer, J W; Craft, S et al. (1999) Age- and dose-dependent glucose-induced increases in memory and attention in schizophrenia. Psychiatry Res 88:1-13 |
