The goal of this proposed research is to determine the neuronal basis of the age-related impairments in attentional abilities, and to test hypotheses about the interactions between the effects of age and benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) release and attentional abilities. Our previous data indicate that: (1) the systemic or intracranial (into the basal forebrain) administration of BZR agonists or inverse agonists impairs or facilitates, respectively, the performance in tasks measuring attentional abilities; (2) BZR ligands bidirectionally modulate cortical ACh efflux; (3) the behavioral and neurochemical effects of BZR ligands interact with age and the activation status of cortical cholinergic afferents; (4) cortical ACh efflux can be measured in performing animals and that performance and release correlate; and (5) cortical infusions of the immunotoxin 192IgG-saporin selectively results in the loss of cholinergic afferents, and that the effects of these lesions on ACh efflux and attentional abilities correspond with the effects of aging. These experiments indicate that valid information about the role of cortical ACh requires the measurement of ACh efflux in animals engaged in behavioral activities which activate cortical cholinergic inputs. The proposed research will measure ACh efflux in differently aged animals while they perform tasks measuring attentional abilities or the effects of the sensorimotor and motivational demands of vigilance tasks. It is predicted that vigilance correlates with cortical ACh efflux, and that the age-related impairments in attentional abilities are associated with a decrease in task- induced cortical cholinergic efflux. Administration of BZR agonists will augment the effects of age. Administration of a BZR selective inverse agonist will facilitate performance and augment the task-induced increase in cortical ACh efflux, particularly in aged animals. The effects of 192IgG-saporin- induced cortical cholinergic deafferentiation will support the hypothesis that this lesion represents a model of the effects of normal aging on cortical ACh. Thus, the proposed research will measure ACh release in task-performing animals and, therefore, will generate valid conclusions on the role of cortical ACh efflux in the effects of age on attentional abilities, the neuronal basis for the increased sensitivity of aged subjects to the cognitive effects of BZR agonists, and on the potential of BZR selective inverse agonists as a therapeutic treatment for the attentional dysfunctions associated with cortical cholinergic hypofunction.
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