PLoS Biol. 2005 Sep;3(9):e299. Epub 2005 Aug 23.

Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates.

Porrino LJ, Daunais JB, Rogers GA, Hampson RE, Deadwyler SA.

Source

Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA.

Abstract

The deleterious effects of prolonged sleep deprivation on behavior and cognition are a concern in modern society. Persons at risk for impaired performance and health-related issues resulting from prolonged sleep loss would benefit from agents capable of reducing these detrimental effects at the time they are sleep deprived. Agents capable of improving cognition by enhancing brain activity under normal circumstances may also have the potential to reduce the harmful or unwanted effects of sleep deprivation. The significant prevalence of excitatory alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamatergic receptors in the brain provides a basis for implementing a class of drugs that could act to alter or remove the effects of sleep deprivation. The ampakine CX717 (Cortex Pharmaceuticals), a positive allosteric modulator of AMPA receptors, was tested for its ability to enhance performance of a cognitive, delayed match-to-sample task under normal circumstances in well-trained monkeys, as well as alleviate the detrimental effects of 30-36 h of sleep deprivation. CX717 produced a dose-dependent enhancement of task performance under normal alert testing conditions. Concomitant measures of regional cerebral metabolic rates for glucose (CMRglc) during the task, utilizing positron emission tomography, revealed increased activity in prefrontal cortex, dorsal striatum, and medial temporal lobe (including hippocampus) that was significantly enhanced over normal alert conditions following administration of CX717. A single night of sleep deprivation produced severe impairments in performance in the same monkeys, accompanied by significant alterations in task-related CMRglc in these same brain regions. However, CX717 administered to sleep-deprived monkeys produced a striking removal of the behavioral impairment and returned performance to above-normal levels even though animals were sleep deprived. Consistent with this recovery, CMRglc in all but one brain region affected by sleep deprivation was also returned to the normal alert pattern by the drug. The ampakine CX717, in addition to enhancing cognitive performance under normal alert conditions, also proved effective in alleviating impairment of performance due to sleep deprivation. Therefore, the ability to activate specific brain regions under normal alert conditions and alter the deleterious effects of sleep deprivation on activity in those same regions indicate a potential role for ampakines in sustaining performance under these types of adverse conditions.

PMID:: 16104830; [PubMed - indexed for MEDLINE]
PMCID: PMC1188239

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Figure 4

Effects of Sleep Deprivation and Sleep Deprivation + CX717

(A) Sleep deprivation condition disrupts DMS performance. Mean percent correct performance across animals for sessions following 30–36 h of sleep deprivation (nine of 11 monkeys in Figure 2A). Plus signs indicate significant mean differences (⁺p < 0.01, ⁺⁺p < 0.001) compared to the respective number of images curve in the normal vehicle condition; dashed line at 60% allows comparison with Figure 2A.
(B) Match response latencies in s (mean ± SEM) sorted for different trial types as in Figure 2B. Asterisks indicate significant difference (*p < 0.01, **p < 0.001) at all delays compared to two-image trials. Plus signs indicate significant differences (⁺p < 0.01, ⁺⁺p < 0.001) compared to same trial types, and dashed line allows comparison with minimum latencies in normal vehicle condition (Figure 2B).
(C) Sleep deprivation + CX717 condition. Effects of administration of CX717 (0.8 mg/kg, IV) 10 min prior to DMS session following 30–36 h of sleep deprivation. Mean (± SEM) percent correct DMS trials for same delay (1–30 sec, in 5-s increments) and #image (two to six) DMS conditions generated by same monkeys tested in (A). Plus signs indicate significant mean differences (⁺p < 0.01, ⁺⁺p < 0.001) compared to the respective number of images curve in the normal vehicle condition (Figure 2A); pound signs (^#p < 0.01,^##p < 0.001) indicate significant differences compared to the same trial types in sleep deprivation condition. Dashed reference line allows comparison with sleep deprivation (A) and normal vehicle conditions (Figure 2A).
(D) Match response latencies for same sleep deprivation + CX717 condition shown in (C), sorted by delay and number of images and labeled as in Figure 2B. Pound signs (^#p < 0.01, ^##p < 0.001) indicate significant differences compared to the same trial types in sleep deprivation condition (A).
DOI: 10.1371/journal.pbio.0030299g004

Facilitation of Task Performance and Removal of the Effects of Sleep Deprivation by an Ampakine (CX717) in Nonhuman Primates

PLoS Biol. PLoS Biol;3(9):e299.

Figure 2

DMS Performance and Match Response Latency under Normal Vehicle and Normal + CX717 Conditions

(A) Normal vehicle condition, mean (± SEM) percent correct DMS performance across 11 monkeys. Each curve reflects percent correct DMS trials sorted by number of images (two to six) in the match phase on trials with different delays (1–30 s plotted in 5-s increments). Performance decreased both as a function of delay and number of images as indicated by separation of curves across delays. “C” on y-axis indicates random or “chance” performance level in task. Asterisks indicate degree of separation from 1–5 s delay trials for significant (*p < 0.01, **p < 0.001) differences, and daggers indicate minimum degree of separation for significance (†p < 0.01, ††p < 0.001) compared to two-image trials.
(B) Match phase response latencies in s (mean ± SEM) for trials shown in (A). Latencies on correct trials were sorted and plotted by number of images at specified delays. Asterisks indicate significant differences (*p < 0.01, **p < 0.001) compared to the mean of two-image trials summed across all delays (dashed line).
(C) Normal + CX717 condition; mean (± SEM) percent correct performance by the same animals as in (A) following administration of CX717 (0.8 mg/kg, IV) prior to start of session. Legend is the same as in (A) for number of images and duration of delay. Performance across both parameters was maximally facilitated as indicated by comparison to dashed line arbitrarily drawn at 60%. Daggers indicate significant difference compared to two-image trials (†p < 0.01, ††p < 0.001). Plus signs indicate significant mean differences (⁺p < 0.01, ⁺⁺p < 0.001) compared to the respective number of images in normal vehicle condition.
(D) Match response latencies in s (mean ± SEM) for normal + CX717 condition sorted by delay and number of images as in (B). Dashed line provides a basis for comparison with minimum latency (1.5 s) in normal vehicle condition (B). Asterisks indicate significant differences (*p < 0.01, **p < 0.001) at all delays compared to two-image trials. Plus signs indicate significant differences (⁺p < 0.01, ⁺⁺p < 0.001) compared to the same trial type in normal vehicle condition (B).
DOI: 10.1371/journal.pbio.0030299g002

Facilitation of Task Performance and Removal of the Effects of Sleep Deprivation by an Ampakine (CX717) in Nonhuman Primates

PLoS Biol. PLoS Biol;3(9):e299.

Figure 9

Multivariate CDA of DMS Performance and Brain CMR_glc Activity

(A) Discriminant functions (DFs 1, 2, and 3) were extracted via CDA from covariance matrices for 12 dependent variables of DMS performance and CMR_glc for nine monkeys across the four treatment conditions (see Materials and Methods). Discriminant scores for each DF (different colored curves) were computed for each animal and treatment condition. Scores were rotated via the CDA for orthogonality, and then standardized with mean of zero, standard deviation ± 1.0, relative to the normal vehicle condition for comparison to the other three test conditions and plotted as means (± SEM) across all animals. Positive mean scores for DF1 indicate increased accuracy (i.e., percent correct trials) and decreased latency in DMS performance, while negative scores indicate decreased accuracy and increased latency. Note that scores for DF2 increased when DF1 increased. Scores for DF3 show only decreases associated with both sleep deprivation conditions. Asterisks indicate significant (*p < 0.01, **p < 0.001) difference compared to normal vehicle score for the respective DF.
(B) A component of the CDA analysis extracted sources of variance associated with changes in absolute CMR_glc (see Materials and Methods) across the six ROIs described in Figures 7 and 8. The length of each bar reflects the total change in CMR_glc measured in that structure (i.e., the ROI). Positive scores indicate relative increases in CMR_glc within a brain region with respect to their levels in the normal vehicle condition (“0”). Negative scores indicate relative decreases in CMR_glc within a brain region. Each colored segment of the bar indicates the proportion of total CMR_glc variance contributed by each of the respective DFs (A) for a given treatment condition: DF1 (orange), DF2 (green), DF3 (blue). Asterisks indicate conditions with significant (*p < 0.01, **p < 0.001) differences in CMR_glc compared to normal vehicle. Height of small black bars at right indicate significance levels for colored segments of bars.
DOI: 10.1371/journal.pbio.0030299g009

Facilitation of Task Performance and Removal of the Effects of Sleep Deprivation by an Ampakine (CX717) in Nonhuman Primates

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