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Mechanisms underlying cognitive enhancement and reversal of cognitive deficits in nonhuman primates by the ampakine CX717

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Abstract

Rationale

Performance of cognitive tasks in nonhuman primates (NHPs) requires specific brain regions to make decisions under different degrees of difficulty or “cognitive load.”

Objective

Local cerebral metabolic activity ([18F]FDG PET imaging) in dorsolateral prefrontal cortex (DLPFC), medial temporal lobe (MTL), and dorsal striatum (DStr) is examined in NHPs performing a delayed-match-to-sample (DMS) task with variable degrees of cognitive load.

Materials and methods

Correlations between cognitive load and degree of brain metabolic activity were obtained with respect to the influence of the ampakine CX717 (Cortex Pharmaceuticals), using brain imaging and recordings of neuronal activity in NHPs and measures of intracellular calcium release in rat hippocampal slices.

Results

Activation of DLPFC, MTL, and DStr reflected changes in performance related to cognitive load within the DMS task and were engaged primarily on high load trials. Similar increased activation patterns and improved performance were also observed following administration of CX717. Sleep deprivation in NHPs produced impaired performance and reductions in brain activation which was reversed by CX717. One potential basis for this facilitation of cognition by CX717 was increased firing of task-specific hippocampal cells. Synaptic mechanisms affected by CX717 were examined in rat hippocampal slices which showed that N-methyl-d-aspartic acid-mediated release of intracellular calcium was reduced in slices from sleep-deprived rats and reversed by application of CX717 to the bathing medium.

Conclusions

The findings provide insight into how cognition is enhanced by CX717 in terms of brain, and underlying neural, processes that are activated on high vs. low cognitive load trials.

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Acknowledgement

The authors thank Michael Todd, Joshua Long, Joseph Noto, Kathryn Gill, Frances Miller, Guillermo Palchik, Michael Dunlap, Santos Ramirez, Ashley Morgan, and Mack Miller for the experimental assistance. This work was supported by NIH DA08549 and MH61397 to R.E.H.; DA06634 and DA09085 to L.J.P.; DA00119, DA023573, DA07625, DA06634, and DARPA (ARO) DAAD19-02-1-0060 to S.A.D.; and Cortex Pharmaceuticals (Irvine, CA, USA). DARPA distribution statement: Approved for public release, distribution unlimited.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC, 27157-1083, USA

    R. E. Hampson, R. A. España, L. J. Porrino & S. A. Deadwyler

  2. Medical School of the Americas, Nevis, West Indies

    G. A. Rogers

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  1. R. E. Hampson
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  2. R. A. España
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Correspondence to S. A. Deadwyler.

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Hampson, R.E., España, R.A., Rogers, G.A. et al. Mechanisms underlying cognitive enhancement and reversal of cognitive deficits in nonhuman primates by the ampakine CX717. Psychopharmacology 202, 355–369 (2009). https://doi.org/10.1007/s00213-008-1360-z

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  • DOI: https://doi.org/10.1007/s00213-008-1360-z

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