The AMPA receptor modulator CX717, given to monkeys engaged in cognitive processing and short-term memory, improved performance in all aspects of the DMS task (see and ). This enhanced performance was evidenced by significant increases in accuracy at all delays and number of images (see ) and was paralleled by reductions in latency to select the correct image during the match phase of the task (see ). In addition to the effects on normal alert performance, the present findings also demonstrated that CX717 removed severe performance deficits produced by subjecting the animals to prolonged periods of sleep deprivation (see ). In conjunction with the effects on behavioral performance, CX717 also affected CMRglc in brain regions engaged while performing the task under normal and/or sleep deprived conditions (see and ). The results show a strong functional relationship between the neurobiological and behavioral effects of the drug and provide insight into how performance in this cognitive task is facilitated by ampakines.
Reports from this and other laboratories have demonstrated enhanced performance by other AMPA receptor modulators under normal alert conditions [6
], one of which employed a task with monkeys similar to the one utilized here [9
]. The current findings extend the basis for the facilitative actions of ampakines to the parallel yet equally sensitive measure, match response latency (see B, D, B, and 4D). The significant modulation of match response latencies by task parameters in the same manner as performance accuracy (percent correct trials) suggests that CX717 also facilitated attentional processes [33
] related to speed of responding on successful trials (A and B), even if the animals were sleep deprived (see D). Since this measure was markedly facilitated by CX717 under normal alert conditions (see ), it likely reflects an increase in accuracy as well as speed of detection of the correct match target.
The marked influence of sleep deprivation on performance (see and ) was paralleled by significant alterations in CMRglc
in DPFC, DStr, precuneate cortex, and MTL (), demonstrating the contribution of a sleep-related factor to brain regions engaged by the DMS task (DF3 in ). It is also evident that both behavioral and brain metabolic processes sensitive to sleep deprivation were affected by administration of CX717 (see and ). Although it is possible that the positive effect of CX717 in sleep-deprived animals was due to an increase in arousal, this explanation is unlikely because of the potent dose-dependent action of the drug in normal animals (see B, ). The performance levels of animals in the sleep deprivation condition were reduced significantly compared to normal vehicle sessions; however, a close examination of latencies (see and ) shows that animals continued to respond in the match phase in a rapid manner (2.5–3.0 sec). The assessment of EEG parameters, although not designed to provide a thorough analysis of sleep architecture, suggests that animals were experiencing microsleep episodes during the sleep deprivation testing condition [30
]. However, these instances did not significantly alter the mean number of trials completed during sessions that were the same duration as normal vehicle tests, nor was the latency to respond to events during the trial elevated more than 1–2 s above normal vehicle sessions (see and ). While preliminary analyses showed that administration of CX717 reduced the incidences of delta and beta band occurrences in sleep-deprived animals (see ), more rigorous assessments of EEG-related changes in the sleep states of the animals will be required to reveal the exact means by which this reversal occurred.
The MTL (including hippocampus) and DPFC have been extensively implicated in both working and short-term memory in monkeys and humans [34
]. The differential changes in CMRglc
in these regions make them strong candidates for the functional substrates of the type(s) of memory process required to successfully perform this DMS task [24
]. Further evidence suggests that the activation of DPFC and MTL reflected utilization of generalized encoding principles shown also in humans [39
]. Although there also exist differences in humans with respect to tasks that are susceptible to sleep deprivation [40
], the fact that performance of this task was severely disrupted, and that both the DPFC and MTL were affected, are consistent with studies in humans showing that repetitive working memory tasks that require a high degree of vigilance are affected by sleep deprivation in a similar manner [41
]. In addition, Benca et al [26
] showed that 24-h sleep architecture was drastically altered in monkeys sustaining lesions of the amygdala, an area possibly contributing to the changes in CMRglc
in the MTL in the current findings.
The detrimental effects on DMS performance of 30–36 h of sleep deprivation in monkeys reported here (see A and ) are difficult to compare directly with different durations of sleep deprivation in humans [16
]. Given the severity and magnitude of the deficit, it is possible that this degree of sleep deprivation in monkeys has more of an effect than in humans more adapted to a 30–36 h (a single night) sleep deprivation period. The current findings are consistent with some reports in humans that show extensive sleep-deprivation-produced deficits in prefrontal-cortex-sensitive cognitive tasks [15
]. However, other reports suggest that complete resolution of these issues will require confirmation that the DMS task employed here is similar to the verbal and/or arithmetic tests used to dissociate different brain regions and circuits in sleep-deprived humans [17
Because of the differential actions in DLPC and DStr versus MTL, it is possible that CX717 influenced the attempts of selective neural circuits to restore total brain activation to a pattern exhibited under normal alert conditions. This would seem logical if additional mechanisms were activated under sleep deprivation conditions to compensate for decreased performance of the task [15
]. Reciprocal changes in DPFC and MTL in the sleep deprivation versus sleep deprivation + CX717 condition may reflect switching between different brain activation patterns as indicated in B. In this regard, the fact that the drug-related regional CMRglc
pattern in sleep-deprived animals resembled the pattern in these same regions observed under normal alert conditions (see ) suggests that the action of CX717 was to revert the brain to a state sufficient to perform the task successfully.
The functional linkage between brain regions engaged by the DMS task and their susceptibility to sleep deprivation and CX717 was demonstrated by the multivariate CDA analysis (), which showed that brain metabolic changes (see F–H and A–C) and behavioral performance (see and ) in each test condition covaried within individual animals [17
]. Three independent sources of variance were extracted from the covariance matrix, and each was determined to result from a major manipulation in the study; DMS task parameters (DF1), presence of CX717 (DF2), and exposure to 30–36 h of sleep deprivation (DF3). The CDA revealed that DF2 and DF3 were additive within individual animals and present when performance (DF1) was reversed in the sleep deprivation + CX717 condition (A). This confirmed that the differential alterations in CMRglc
in specific brain regions by sleep deprivation (DPFC, DStr, and MTL; ) were specific to CX717 action in sleep-deprived animals (B), suggesting that these areas were linked with respect to susceptibility to sleep deprivation and CX717 effects [17
Although the finding that separate brain regions (DPFC, DStr, and MTL) were differentially altered by sleep deprivation (see ) is consistent with several human studies [15
], recent reports indicate that generalization of such deficits to other circumstances and tasks is not straightforward [18
]. The demands of sleep deprivation most likely engage different processes depending on both the type and the difficulty of the task [17
]. It has been suggested that (1) different brain “circuits” may be activated under sleep deprivation conditions that are not engaged under normal conditions when performing the same tasks [17
], and (2) that such demands are expressed differently depending on the specific regions that are “recruited” to perform the task [40
]. At this time it is not possible to know whether such factors are similarly expressed with respect to sleep deprivation in nonhuman primates. The differential nature of the disruption in CMRglc
across different brain regions shown here, however, suggests that compensatory processes may have been involved.
The one brain area in which the effects of sleep deprivation were not ameliorated by CX717 was the thalamus, which showed very different CMRglc
patterns in all conditions compared to DPFC, DStr, precuneate cortex, and MTL (B). While CMRglc
in the thalamus has been reported to be affected in sleep deprivation [17
] other reports using functional magnetic resonance imaging actually found increased thalamic activation in sleep-deprived humans [15
]. The lack of responsiveness to CX717 under either normal or sleep deprivation conditions in the present study (B), however, provides new information regarding mechanisms of sleep regulation by the thalamus. The thalamic reticular nucleus, a major synchronizing influence on cortical EEG, contains clusters of electrically coupled neurons [46
], which may not be directly affected by an AMPA receptor modulator such as CX717. This lack of direct synaptic influence could explain the sustained decrease in thalamic CMRglc
in the sleep deprivation + CX717 condition, and perhaps also why the associated behavioral performance (see B) did not reverse to levels exhibited in the normal + CX717 condition (see B).
Several investigations have shown that sleep deprivation down-regulates glutamatergic as well as other synaptic and receptor-mediated events in cortical neurons [47
]. Ampakines modify ionic current through glutamate-gated channels with differential effectiveness across AMPA receptor subtypes, primarily by modulating desensitization and slowing channel closing [3
]. The involvement in sleep and wakefulness of glutamatergic synapses along with several other neurotransmitter systems has been addressed in several studies [52
]. AMPA receptor stimulation in the nucleus basalis of Meynert has been implicated in the activation of inhibitory projections from this nucleus to other brain regions as the basis for decreasing a particular type of sleep pattern [53
]. Functional AMPA receptors have been shown in most of the affected brain regions described here [14
]; hence, their enhancement by an agent such as CX717 could compensate for down-regulated glutamatergic systems in sleep-deprived subjects [50
]. Another important neurotransmitter involved in sleep-waking cycles is orexin, a peptide that prevents sleep in narcoleptic dogs and has also been shown to release glutamate [52
]. Consequently, the sleep-preventing effects of orexin may be potentiated by CX717. Ampakines, therefore, have the capability to positively modulate many different glutamatergic circuits and pathways in several pertinent brain regions [11
], thereby increasing the potential to counteract cognitive deficits under normal as well as sleep deprivation conditions [16
Other compounds that have been utilized to combat the effects of sleep deprivation, including psychostimulants (amphetamine), caffeine, and modafinil [58
] act through different, non-AMPA receptor-mediated, cell signaling pathways. The usefulness of these agents, however, may be limited due to their potential for addiction and/or their potent stimulant actions, which can distort cognitive and sensory processes at doses required to counteract the effects of sleep deprivation [58
In this investigation, the ampakine CX717 improved performance under both normal and sleep deprivation conditions in a nonhuman primate model. The effects on performance were accompanied by significant changes in local glucose metabolism in brain regions implicated in this type of cognitive processing. Selective activation of these brain regions over others during performance of the task, and reciprocal modulation by CX717 versus sleep deprivation, are key supportive outcomes of this study. The fact that ampakines such as CX717 can temporarily alleviate the effects of prolonged periods of sleep deprivation, even to the extent of improving performance above normal levels, indicates their potential applicability to many circumstances in which human performance is compromised by extensive sleep loss.