Role of Adenosine A1 Receptor in Sleep Deprivation-Induced Neuroinflammation: Insights on Rapid Eye Movement Sleep and Fear Extinction Memory Recall in Rats

Administration of CPT during SD reversed extinction recall impairments (p = 0.01), improved line crossings in OFT, sucrose preference (p < 0.01), and reduced immobility during the FST (p < 0.01). Immunohistochemical analysis of DG, CA3, and CA1 regions of the hippocampus revealed a significant upregulation of A1R expression in the SD and SD+CPT groups (p < 0.001, n = 5). Expression of post-synaptic density protein (PSD-95) and synaptophysin increased and a marked reduction in the Toll-like receptor-4 (TLR-4) expression in activated microglia in the SD+CPT group. 8-CPT partially restored SD-induced decline in serotonin and brain-derived neurotrophic factor. SD-induced neuronal apoptosis through caspase-3 and the P-p38 mitogen-activated protein kinase pathway was partially reversed by 8-CPT. RT-PCR results showed that A1R antagonism attenuated gene expression of pro-inflammatory cytokines (IL-1β, TNFα, p-NFκB s536, and IL-6) and increased anti-inflammatory cytokines (IL-1ra, IL-4, IL-10, IL-11, and IL-13) during SD. EEG recordings revealed that A1R antagonism increased REM sleep without affecting non-REM sleep during SD, leaving rebound sleep unaffected. Conclusion: These findings highlight the role of A1R antagonism in restoring fear extinction memory recall, synaptic plasticity, adult neurogenesis, neuronal cell death, and attenuating neuroinflammation during SD, paving the way for the further exploration of its therapeutic potential in sleep-related cognitive deficits.