NEUROPHARMACOLOGIC CHALLENGES IN DEMENTIA

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The overall goal of this project is to understand better how alterations in glutamatergic transmission modify cognition and behavior in patients with dementia. This information can help determine whether NMDA antagonists might be used to treat neurodegenerative disorders. Already, there is considerable evidence that activation of NMDA glutamatergic receptors mediate long term potentiation, which may be the physiological basis for learning and memory. There is also considerable evidence that neurons containing these receptors are damaged in patients with Alzheimer's disease (AD) and Huntington's disease (HD), and that glutamate may contribute to the pathogenesis of these disorders by acting as an excitotoxin. Nevertheless, the role of glutamatergic neurons upon human cognition and behavior, and the relationship between the damage of these neurons and the symptomatology of AD is unclear. Furthermore, almost all human trials have been concerned only with the acute effects of NMDA antagonists rather than the effects of prolonged administration. This lack of knowledge and concern about possible adverse effects have inhibited the development of NMDA antagonists as potential neuroprotective agents. Tolerance to some adverse effects of these drugs may develop with continued exposure and it may be possible to block adverse effects with GABA-A agonists, perhaps by altering pathways in the cingulate cortex. We will study the dose dependent effects on cognition and behavior of acute and prolonged infusions of the non- competitive NMDA antagonist ketamine in aged normal subjects and in patients with HD and AD using doses of intravenous ketamine previously shown to be safe in patients with AD. This will help us determine whether AD patients are more sensitive than other groups to cognitive changes caused by NMDA antagonists. Next, we will compare the effects induced by acute (1-2 hour) and prolonged (up to 12 hour) infusions of ketamine in patients with AD to examine further the possibility that tolerance to this drug develops. Finally, we will test whether the adverse behavioral reactions of these drugs can be avoided by determining whether treatment with non-sedating doses of the GABA A agonist phenobarbital attenuates the adverse behavioral effects induced by ketamine. A better understanding of the cognitive and behavioral effects of glutamatergic antagonists will clarify how glutamate might contribute to the expression of Alzheimer's disease and help develop approaches so that these drugs could be used to treat neurodegenerative disorders.