This proposal covers three main research areas: (I) the behavioral functions of frontal cortex acetylcholine (ACh), particularly its involvement in attentional abilities; (II) the bidirectional modulation of attentional abilities and of cortical ACh release by compounds that regulate GABAergic transmission (i.e., benzodiazepine receptor [BZR] agonists and selective inverse agonists), and the determination of the neuronal substrates of these GABA-cholinergic interactions and of the cognitive effects of BZR-ligands; (III) the age-related changes in attentional abilities and in the regulation of cortical ACh release, and the BZR-agonist-induced exacerbation and the BZR-selective inverse agonist-induced attenuation of these effects of age. Methodologically, experiments will be conducted using operant behavioral paradigms for the measurement of sustained and divided attention, the technique of bilateral intracranial infusion of compounds in performing animals, and the microdialysis technique for the measurement of ACh release in awake, freely moving animals. Furthermore, as our previous data have indicated that BZR-mediated modulation of cortical ACh release is a function of the activational status of cortical cholinergic afferents, interactions between attentional performance, the effects of BZR-ligands, and cortical ACh release will be studied by dialyzing animals while they perform in attentional tasks (or in behavioral procedures that control for the sensory effects of stimuli and for the motor components of the response requirements). Taken together, the results from this research will add to our understanding of the neuronal mechanisms of attentional abilities and of the behavioral and neuronal components of BZR-agonist-induced impairments of these abilities. Furthermore, this research will test hypotheses about the neuronal mechanisms involved in the increased vulnerability of the elderly to the detrimental cognitive effects of BZR- agonists. Finally, the proposed experiments will examine the hypotheses that the treatment with BZR-selective inverse agonists results in the facilitation of attentional abilities, and that the beneficial behavioral effects of such compounds depend on their potency to enhance the ability of cortical cholinergic afferents to respond to stimulation, particularly in aged subjects.
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