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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Schools of Arts and Sciences
United States
Zip Code
Sarter, Martin; Bruno, John P (2004) Developmental origins of the age-related decline in cortical cholinergic function and associated cognitive abilities. Neurobiol Aging 25:1127-39
Herzog, Christopher D; Nowak, Kelly A; Sarter, Martin et al. (2003) Microdialysis without acetylcholinesterase inhibition reveals an age-related attenuation in stimulated cortical acetylcholine release. Neurobiol Aging 24:861-3
Sarter, Martin; Bruno, John P (2002) The neglected constituent of the basal forebrain corticopetal projection system: GABAergic projections. Eur J Neurosci 15:1867-73
Sarter, M; Turchi, J (2002) Age- and dementia-associated impairments in divided attention: psychological constructs, animal models, and underlying neuronal mechanisms. Dement Geriatr Cogn Disord 13:46-58
Burk, Joshua A; Herzog, Christopher D; Porter, M Christine et al. (2002) Interactions between aging and cortical cholinergic deafferentation on attention. Neurobiol Aging 23:467-77
Turchi, J; Sarter, M (2001) Antisense oligodeoxynucleotide-induced suppression of basal forebrain NMDA-NR1 subunits selectively impairs visual attentional performance in rats. Eur J Neurosci 14:103-17
Turchi, J; Sarter, M (2001) Bidirectional modulation of basal forebrain N-methyl-D-aspartate receptor function differentially affects visual attention but not visual discrimination performance. Neuroscience 104:407-17
Sarter, M; Givens, B; Bruno, J P (2001) The cognitive neuroscience of sustained attention: where top-down meets bottom-up. Brain Res Brain Res Rev 35:146-60
Turchi, J; Sarter, M (2000) Cortical cholinergic inputs mediate processing capacity: effects of 192 IgG-saporin-induced lesions on olfactory span performance. Eur J Neurosci 12:4505-14
Sarter, M; Podell, M (2000) Preclinical psychopharmacology of AIDS-associated dementia: lessons to be learned from the cognitive psychopharmacology of other dementias. J Psychopharmacol 14:197-204

Showing the most recent 10 out of 45 publications