Caffeine and modafinil promote adult neuronal cell proliferation during 48 h of total sleep deprivation in rat dentate gyrus

Exp Neurol. 2013 Oct:248:470-81. doi: 10.1016/j.expneurol.2013.07.021. Epub 2013 Aug 3.


It has been established that sleep deprivation (SD) reduces the proliferation of neuronal precursors in the adult hippocampus. It has also been reported that psychostimulant drugs modulate adult neurogenesis. We examined the modulatory role of two psychostimulant drugs modafinil and caffeine on adult neuronal cell proliferation (NCP) during 48 h of total SD. A novel automated cage shaking stimulus was used to induce SD based on animal activity. 5-Bromo-2″-deoxyuridine (BrdU; 50mg/kg/day i.p.) was injected at the onset of the light phase for two days. Rats were successfully sleep deprived for 85-94% of total time. Stereological analysis showed that both caffeine and modafinil treatments during SD improved the number of BrdU positive cells as compared to the SD group. Caffeine treatment during SD, significantly increased early proliferative and post-mitotic stages of doublecortin (DCX) positive cells while modafinil treatment during SD, increased intermediate and post-mitotic stages of DCX positive cells compared to SD+Vehicle group. Brain-Derived Neurotrophic Factor (BDNF) expression on BrdU positive cells as well as in the dentate gyrus (DG) region was decreased significantly after sleep deprivation. Both caffeine and modafinil significantly improved BDNF expression in the DG region. Modafinil, but not caffeine, significantly decreased hippocampal adenosine level during SD in comparison to the SD+Vehicle group. It may be concluded that caffeine or modafinil treatment during 48 h of SD prevents the SD induced decline in neuronal proliferation and differentiation. Caffeine and modafinil induced alterations of NCP during SD may involve modulation of BDNF and adenosine levels.

Keywords: 3,3′-diaminobenzidine; AC; ANOVA; Ad A1; Adenosine; Adult neuronal cell proliferation; BDNF; Brain-Derived Neurotrophic Factor; BrdU; CC; Caffeine; DAB; DCX; DG; EEG; EMG; GFAP; Gt; HC; HPLC; HRP; Modafinil; Ms; NCP; NREM; PBS; PDE; PFA; REM; RT; Rb; Rt; SD; SD+CAF; SD+MDF; SDS; SEM; Sleep deprivation; adenosine A1 receptor; adult neuronal cell proliferation; analysis of variance; apparatus control; bromodeoxyurdine; cage control; dentate gyrus; doublecortin; electroencephalogram; electromyogram; glial fibrillary acidic protein; goat; high pressure liquid chromatography; hippocampus; horseradish peroxidase; mouse; non-rapid eye movement; paraformaldehyde in PBS; phosphate buffered saline; phosphodiesterase; rabbit; rapid eye movement; rat; room temperature; sleep deprivation; sleep deprivation syndrome; sleep deprived for 48h and caffeine treated; sleep deprived for 48h and modafinil treated; sleep deprived for 48h and saline treated; standard error of mean.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Brain-Derived Neurotrophic Factor / metabolism
  • Caffeine / pharmacology*
  • Cell Count
  • Cell Proliferation / drug effects*
  • Central Nervous System Stimulants / pharmacology*
  • Corticosterone / blood
  • Dentate Gyrus / cytology
  • Dentate Gyrus / drug effects*
  • Dentate Gyrus / metabolism
  • Doublecortin Protein
  • Male
  • Modafinil
  • Neurons / drug effects*
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sleep Deprivation / metabolism*


  • Benzhydryl Compounds
  • Brain-Derived Neurotrophic Factor
  • Central Nervous System Stimulants
  • Dcx protein, mouse
  • Dcx protein, rat
  • Doublecortin Protein
  • Caffeine
  • Modafinil
  • Corticosterone