Differential Effects of Nicotinic, Glutamatergic, and Conventional Wakefulness Agents on Cognition on a Murine Model of Acute Severe Sleep Deprivation

Güvel M. C., Aykan U., Paykal G., Uluoğlu C.

CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS, 2026 (SCI-Expanded, Scopus)

Özet

Objective Sleep deprivation poses critical safety risks in high-stakes professions, where traditional stimulants often fail to sustain cognitive performance. Addressing the need for novel cognitive enhancers, this study compared the effects of modafinil and caffeine with novel nicotinic (AVL-3288) and glutamatergic (CX516) positive allosteric modulators on behavior and memory in severely sleep-deprived mice.Methods Male C57BL/6 mice underwent 48 hours of paradoxical sleep deprivation before receiving intraperitoneal doses of modafinil (300 mg/kg), caffeine (10 mg/kg), AVL-3288 (1, 2 mg/kg), CX516 (40, 80 mg/kg), or vehicle. A behavioral test series assessed locomotor activity (Open Field), anxiety (Elevated Plus Maze), reward-based working and spatial memory (Eight-Arm Radial Maze), escape-based spatial memory (Barnes Maze), and depressive mood (Tail Suspension).Results Modafinil markedly increased locomotor activity and suppressed appetite. Caffeine, AVL-3288 (1 mg/kg), and CX516 (40 mg/kg) improved reward-based working memory (Eight-Arm Radial Maze). However, these same agents impaired performance in the escape-based spatial reference memory task (Barnes Maze). No mood-altering effects were observed. The novel modulators displayed complex, non-dose-dependent profiles.Discussion Under severe sleep deprivation, specific wakefulness-enhancing substances can yield contrasting outcomes, enhancing reward-associated memory while negatively affecting escape-associated memory. These divergent outcomes suggest that neuromodulation during severe sleep deprivation exerts task-dependent behavioral effects, though the precise mechanisms driving the differences between the two maze paradigms remain to be elucidated.Conclusion Pharmacological interventions under severe sleep deprivation can produce complex, bidirectional effects on cognition. This highlights that cognitive enhancement is likely task-dependent rather than global, necessitating a comprehensive assessment of diverse behavioral domains.