Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2005 Sep;3(9):e299.
doi: 10.1371/journal.pbio.0030299. Epub 2005 Aug 23.

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

Linda J Porrino  1 , James B Daunais, Gary A Rogers, Robert E Hampson, Sam A Deadwyler
Affiliations

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

Linda J Porrino et al. PLoS Biol. 2005 Sep.

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Multi-Image Visual DMS Task
DMS trials consist of four phases. In the first, the start-trial phase, a circle was displayed to initiate the trial. The monkey had to move the cursor into the circle to initiate presentation of the sample image. Next, in the sample phase, a single “sample” clip art image (red star) was presented. Movement of the cursor into the sample image blanked the screen and initiated the delay phase. In this third phase, delay, the screen was blanked for a 1–30 s interval (randomly selected on each trial); the match phase was initiated automatically at the end of delay phase. In the last, match phase, the sample image was presented simultaneously with one to five other randomly chosen “nonmatch” images. Images could appear randomly at any of nine spatially distinct screen locations. The sample image always appeared at a different location in the match phase, and monkeys were required to place the cursor in the sample image for 200 ms or longer to be rewarded and terminate the trial. Movement of cursor into a nonmatch image for 200 ms or longer terminated the trial with no reward. Each clip-art image (including samples and nonmatches) was selected from a list of 5,000 clip art images and presented only once, such that all trials were unique with no repetition of images during the session. The intertrial interval was 10 s, in which the screen was blank prior to the appearance of the start-trial circle. DOI: 10.1371/journal.pbio.0030299g001
Figure 2
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
Figure 3
Figure 3. Effects of Different Doses of CX717 on DMS Performance in Normal + CX717 Condition
(A) CX717 is shown administered on consecutive sessions for nine monkeys over three dose ranges of CX717 (0.3–0.5 mg/kg, 0.8–1.0 mg/kg, and 1.5 mg/kg, IV). Each CX717 session (C, arrows) was interspersed with a single normal vehicle (V) session. Curves show mean (± SEM) percent correct performance over the entire session from each different monkey, as indicated by separate symbols. Arrows indicate CX717 sessions (also denoted by “C” on axis). Note escalating doses (0.3, 0.8, and 1.5 mg/kg) shown were in four of the nine monkeys. (B) Performance on split sessions (n = 4 monkeys) in which vehicle was administered at the start of the DMS session, and midway through same session CX717 (0.8 mg/kg, IV) was administered via remote pump without interruption. Mean (± SEM) percent correct performance over at least 50 trials was calculated separately for the first half (vehicle) and second half (CX717, 0.8 mg/kg) of the same session. Asterisks indicate a significant (** p < 0.001) increase in the second half of the session relative to the first (vehicle). (C) Overall mean dose-effect relationship of CX717 on normal alert DMS performance across monkeys (n = 9) in sessions in which each of the three doses (0.3, 0.8, and 1.5 mg/kg, IV) was administered. DMS sessions in which the three doses were received in an escalating order were compared with sessions in which the same doses were administered in a randomized order (F[1,50] = 2.31, p = 13.5, NS). Asterisks indicate significant (*p < 0.01, **p < 0.001) difference relative to vehicle sessions. DOI: 10.1371/journal.pbio.0030299g003
Figure 4
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
Figure 5
Figure 5. Separation of Effects of Sleep Deprivation + CX717 on DMS Performance Parameters, Delay Versus Number of Images
(A) Mean (± SEM) percent correct performance across animals on DMS trials sorted by delay (1–30 sec, in 5 s increments) and summed over two to six image trials for normal vehicle, normal + CX717, sleep deprivation, and sleep deprivation + CX717 conditions (separate curves). Data are the same as shown in Figures 2 and 4. (B) Mean (± SEM) percent correct performance for DMS trials partitioned by number of images and summed over 1–30 s delays for the same four treatment conditions shown in (A). Asterisks indicate separation limits for significant differences (*p < 0.01, **p < 0.001) of CX717 and sleep deprivation means compared to the normal vehicle mean; § symbol indicates that all points on the indicated curve differ significantly from all points on normal vehicle curve. DOI: 10.1371/journal.pbio.0030299g005
Figure 6
Figure 6. EEG and PSD Measures in Sleep-Deprived Monkeys
Measures superimposed (n = 4) are average PSD (upper graphs) and individual sample EEGs (lower tracings), recorded from electrodes placed over the parietal cortex, shown for three different treatment conditions (left, normal vehicle; middle, sleep deprivation; and right, sleep deprivation + CX717). In the graphs (upper) are shown PSDs for EEGs recorded from animals performing the DMS task. Sleep deprivation condition (middle) shows increased power of high-amplitude, slow-wave delta band (0.5–5 Hz, above dotted line) and two prominent peaks in the beta band (18–25 Hz) at 20 and 25 Hz (asterisks) relative to the normal vehicle condition (left). Reduction of sleep deprivation features of PSD in same animals following administration of CX717 (0.8 mg/kg) is indicated at right by a decrease in PSD delta band (0.5–5 Hz, dotted line) and reduction in power of peaks (asterisks) in the beta band (18–25 Hz). PSDs were calculated as log of root-mean-square power in 10-min segments of EEG recordings, using frequency increments of 0.25 Hz, plotted separately for four monkeys in each condition (individual traces). In the tracings (lower) are shown EEG segments (4.0 s) recorded from one of five electrode locations on the surface of the parietal cortex to demonstrate different EEG frequencies present in each condition. Traces correspond to the respective DMS testing sessions shown in the PSD plots above. DOI: 10.1371/journal.pbio.0030299g006
Figure 7
Figure 7. SPM Maps of Brain Regions Showing Changes in Regional CMRglc during Performance of DMS Task for Normal Vehicle and Normal + CX717 Conditions
(A–E) Maps are shown for the comparison of CMRglc during DMS performance in the normal vehicle to the baseline, no-task condition. CMRglc was significantly increased during normal vehicle condition compared to baseline, no-task condition. (F–H) Maps are shown for the comparison of CMRglc during DMS performance in the normal + CX717 condition to normal vehicle condition. CMRglc was increased following the administration of CX717 (0.8 mg/kg, IV) as compared to normal vehicle condition (C–E). Regional changes are displayed on both horizontal section (A) and coronal sections (B–H) of MR images of rhesus monkey brain at the level of the motor and premotor cortex (A and B), DPFC (C and F), MTL (D and G), and parietal cortex (E and H). Statistical parametric maps were generated using SPM99 software. Colors indicate the location of clusters with a height (magnitude) threshold of p < 0.05 and spatial extent greater than 50 voxels. Color bar indicates t values for the comparisons (red, t = 2.0, p < 0.05; yellow, t = 5.0, p < 0.001). Note: left and right half of hemisphere are shown on left and right of images respectively. Area 6, premotor cortex; Cere, cerebellum; FEF, frontal eye fields; Prec, precuneus; S1, primary somatosensory cortex. DOI: 10.1371/journal.pbio.0030299g007
Figure 8
Figure 8. SPM Maps of Brain Regions Showing Changes in Regional CMRglc During Performance of DMS Task for Sleep Deprivation and Sleep Deprivation + CX717 Conditions
(A–C) Maps are shown for the comparison of CMRglc during DMS performance in sleep deprivation to normal vehicle conditions (see Figure 7C–7E). Decreases (blue) are shown for DPFC (A), DStr (B), and thalamus (Thal; C). Increases in CMRglc (orange and yellow) are shown in C for MTL. (D–F) Maps shown for comparison of CMRglc during DMS performance in sleep deprivation + CX717 (0.8 mg/kg, IV) to the sleep deprivation condition. Increases in CMRglc were observed in DPFC (D) and DStr (E), whereas decreases were observed in MTL (F). Absence of labeled voxels for thalamus (Thal) in (F) indicates no change from sleep deprivation (C above) versus sleep deprivation + CX717 conditions. Regional changes are displayed on coronal sections of MR images of rhesus monkey brain at the level of the DPFC (A,D), DStr (B,E) and MTL (C,F). Statistical parametric maps were generated using SPM99 software. Colors indicate the location of clusters with a height threshold of p < 0.05 and spatial extent greater than 50 voxels. Color bars indicate t values (2–5; corresponding to p < 0.05 to p < 0.001, respectively) for significance of increase (red-yellow) or decrease (blue-green) in comparisons. Left and right hemispheres are on the left and right of images respectively. DOI: 10.1371/journal.pbio.0030299g008
Figure 9
Figure 9. Multivariate CDA of DMS Performance and Brain CMRglc Activity
(A) Discriminant functions (DFs 1, 2, and 3) were extracted via CDA from covariance matrices for 12 dependent variables of DMS performance and CMRglc 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 CMRglc (see Materials and Methods) across the six ROIs described in Figures 7 and 8. The length of each bar reflects the total change in CMRglc measured in that structure (i.e., the ROI). Positive scores indicate relative increases in CMRglc within a brain region with respect to their levels in the normal vehicle condition (“0”). Negative scores indicate relative decreases in CMRglc within a brain region. Each colored segment of the bar indicates the proportion of total CMRglc 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 CMRglc 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
See this image and copyright information in PMC

References

    1. Schmitt WB, Sprengel R, Mack V, Draft RW, Seeburg PH. Restoration of spatial working memory by genetic rescue of GluR-A-deficient mice. Nat Neurosci. 2005;8:270–272. - PubMed
    1. Rumpel S, Ledoux J, Zador A, Malinow R. Postsynaptic receptor trafficking underlying a form of associative learning. Science. 2005;308:83–88. - PubMed
    1. Suppiramaniam V, Bahr BA, Sinnarajah S, Owens K, Rogers G. Member of the Ampakine class of memory enhancers prolongs the single channel open time of reconstituted AMPA receptors. Synapse. 2001;40:154–158. - PubMed
    1. Arai AC, Kessler M, Rogers G, Lynch G. Effects of the potent ampakine CX614 on hippocampal and recombinant AMPA receptors: Interactions with cyclothiazide and GYKI 52466. Mol Pharmacol. 2000;58:802–813. - PubMed
    1. Arai AC, Xia YF, Rogers G, Lynch G, Kessler M. Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action. J Pharmacol Exp Ther. 2002;303:1075–1085. - PubMed

Publication types

MeSH terms

LinkOut - more resources