The proposed research will focus on two different interactions between benzodiazepine receptor ligands and age-related behavioral and neuronal changes. First, although benzodiazepine receptor agonists (BZRa) are the most often used psychotropic drugs in the elderly, and are known to impair cognitive abilities, their interactions with age-related behavioral and neuronal changes have yet to be characterized. The proposed research will test the hypotheses that BZRa and aging act synergistically to compromise attentional abilities. We will determine whether this interaction is based on the GABAergic innervation of functionally declining cholinergic neurons originating in the basal forebrain and innervating cortex. Second, benzodiazepine receptor ligands that exert effects opposite to BZRa (i. e. , benzodiazepine receptor antagonists/ partial inverse agonists) have been demonstrated to attenuate behavioral impairments associated with disruptions in cholinergic systems. The proposed research will extend these findings to the attentional impairments associated with normal aging, and will test the hypothesis that the beneficial behavioral effects of such treatments are mediated via an increase in cortical acetylcholine release. These effects are presumably based on an inhibition of normal GABA-cholinergic interactions in the basal forebrain. These experiments will employ computerized operant conditioning techniques for the testing of attentional abilities in rats of different ages, systemic and intracranial administration of drugs in freely moving animals, and microdialysis for the measurement of cortical acetylcholine release. Thus, the proposed research will contribute to the understanding of the behavioral and neuronal consequences of the use of BZRa in the elderly, and will outline the behavioral and neuronal potential of a novel pharmacological approach for the treatment of age-related cognitive impairments.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Biochemical Endocrinology Study Section (BCE)
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Ohio State University
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United States
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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

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