In vivo screening of cholinergic cognition enhancers

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DESCRIPTION (provided by applicant): This R21 application seeks support for the development of a novel screening procedure for candidate therapeutics for the treatment of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Productive and informative screening procedures for the detection and characterization of the pro-cognitive and pro-cholinergic properties of putative treatments have remained scarce. The proposed project is designed to investigate the usefulness of a new in vivo screening procedure for the detection and characterization of cognition enhancers acting by, at least in part, increasing prefrontal cholinergic activity. This procedure allows the demonstration of transient cholinergic activity evoked by cues triggering attentional processes. The modulatory effects of candidate drugs on cue-evoked cholinergic activity ("cholinergic footprints") and associated effects on performance are hypothesized to serve as effective screening tools for cognition enhancers. The experiments of Aim 1 will demonstrate that differential ""cholinergic footprints"" are generated by major reference compounds, including amphetamine, nicotine, d-cycloserine and thioperamide. Aim 2 will demonstrate that this screening procedure can be employed to characterize and differentiate the effects of antipsychotic drugs hypothesized to exhibit differential pro-cognitive effects in an animal model of schizophrenia. Future screening of compounds with differential affinity to receptor subtypes, such as subtypes of cholinergic, noradrenergic, or glutamatergic receptors, will demonstrate that differential "cholinergic footprints" are generated by receptor subtype-selective compounds. Furthermore, the characteristics of an "optimal cholinergic footprint" for receptor subtype-selective compounds will be defined for use as a reference for further screening. The long-term goal of this research is to demonstrate that the proposed experimental paradigm serves as an effective screening test for use in programs designed to develop cognition enhancers. Thus, this research will contribute to the development of more effective preclinical strategies for the detection and development of cognition enhancers. Relevance The development of treatments for the cognitive impairments associated with schizophrenia, the dementias and other neuropsychiatric and neurodegenerative disorders has been lacking informative, effective and productive preclinical methods for the detection and characterization of new treatments. As efforts to develop cognition enhancers have focused on drugs modulating forebrain cholinergic neurotransmission, the proposed research is designed to develop and validate a new in vivo screening method for cognition enhancers acting via stimulating prefrontal cholinergic activity. The development of new drug finding