Benzodiazepine receptor agonists (BZRa) are well known to induce anterograde amnesia in humans and animals. It has been speculated that changes in stimulus attention and processing represent a major component of this disruption of learning. Indeed, BZRa have been demonstrated to impair the ability to attend to stimuli, particularly in situations which require the subject to detect rarely and unpredictably occurring signals. The proposed research will examine the hypothesis that the effects of BZRa on vigilance represent a specific pharmacological property which is dissociable from effects on locomotor activity and sedation. The major part of the proposed experiments will test the hypothesis that the attentional and locomotor effects of BZRa and partial agonists are mediated via anatomically distinct areas of the brain. The search for these brain areas will be initially guided by findings which suggest that areas preferably enriched with BZ1-receptor subtypes (e.g., globus pallidus) are involved in the locomotor effects, whereas regions characterized by high densities of BZ2-binding sites (e.g., dentate gyrus) mediate the attentional impairments produced by compounds such as chlordiazepoxide (CDP). Rats will be trained in visual signal detection tasks. The effects of systemic administration of the BZ 1-selective zolpidem, the non-se dative partial agonist Rol6-6O28, and the full agonist CDP will be studied in order to characterize the components of the vigilance impairment typically induced by BZRa. Using the technique of intracranial injections in behaving animals, the effects of bilateral infusions of these compounds on task performance will be studied. The regions selected include the globus pallidus, dentate,gyrus, basolateral amygdala, caudate nucleus, substantia innominata, and locus coeruleus. This research will extend our understanding about the behavioral and neuronal mechanisms involved in the effects of BZRa and contribute to the characterization of GABAergic systems involved in these effects.
