Psychotropic drugs are commonly used in the elderly, and their use is associated with substantial morbidity due to drug toxicity and interactions. Toxicity occurs in part due to enhanced sensitivity to drugs in the elderly. Enhanced sensitivity has been reported for benzodiazepines, tricyclic antidepressants, opiates, barbiturates, caffeine, and antihistamines. Although for several drugs sensitivity appears to be due to pharmacokinetic factors, for most drug classes age-related kinetic changes are limited. Since most psychotropic agents interact with neurotransmitter receptors, it is likely that enhanced sensitivity to psychotropic drugs in the elderly is, at least in part, related to receptor interactions or post-receptor events. Prior studies indicate age-related changes in several neurotransmitter systems. To elucidate receptor contributions to enhanced drug sensitivity, we have chosen the benzodiazepine/GABA system as an initial model. Benzodiazepines are commonly used in the elderly and their use is associated with morbidity due to falls and cognitive impairment. Detailed pharmacokinetic studies indicate limited changes with age. Our initial findings indicate no significant age-related alterations in binding or function at the GABAA receptor complex in a mouse model. However, preliminary data indicate two potentially important neurochemical alterations in aged animals which may contribute to enhanced benzodiazepine sensitivity: 1. Decreased benzodiazepine receptor synthetic rate in aged mice; 2. Decreases in GABAA receptor gene expression in aged mice. Our major hypotheses are: 1. Aging is associated with alterations in benzodiazepine receptor synthetic rate and GABAA receptor gene expression; and 2. These alterations contribute to age-related differences in responses to chronic drug administration. Across a broad range of the animal lifespan, studies will examine benzodiazepine receptor synthetic rate and GABAA receptor gene expression in major brain regions and the effects of chronic benzodiazepine administration on GABAA receptor binding and function, benzodiazepine receptor synthetic rate and GABAA receptor gene expression. These studies will serve as a model for additional studies of other neurotransmitter systems; subsequent studies will examine the serotonergic system, and in particular effects of aging on 5HTlA receptor synthetic rate and on binding responses to chronic buspirone administration.
