Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation

Br J Pharmacol. 2012 Mar;165(6):1904-1913. doi: 10.1111/j.1476-5381.2011.01689.x.


Background and purpose: Prolonged wakefulness impairs sustained vigilant attention, measured with the psychomotor vigilance task (PVT), and induces a compensatory increase in sleep intensity in recovery sleep, quantified by slow-wave activity (SWA) in the sleep electroencephalogram (EEG). These effects of sleep deprivation are counteracted by the adenosine receptor antagonist caffeine, implying involvement of the adenosine neuromodulator/receptor system. To examine a role for adenosine A(2A) receptors, we investigated whether variation of the A(2A) receptor gene (ADORA2A) modified effects of caffeine on PVT and SWA after sleep deprivation.

Experimental approach: A haplotype analysis of eight single-nucleotide polymorphisms of ADORA2A was performed in 82 volunteers. In 45 young men carrying five different allele combinations, we investigated the effects of prolonged waking and 2 × 200 mg caffeine or 2 × 100 mg modafinil on psychomotor vigilance, sleepiness, and the waking and sleep EEG.

Key results: Throughout extended wakefulness, the carriers of haplotype HT4 performed faster on the PVT than carriers of non-HT4 haplotype alleles. In haplotype HT4, caffeine failed to counteract the waking-induced impairment of PVT performance and the rebound of SWA in recovery sleep. However, caffeine was effective in non-HT4 allele carriers, and modafinil reduced the consequences of prolonged waking, independently of ADORA2A haplotype.

Conclusions and implications: Common genetic variation of ADORA2A is an important determinant of psychomotor vigilance in rested and sleep-deprived state. It also modulates individual responses to caffeine after sleep deprivation. These findings demonstrate a role for adenosine A(2A) receptors in the effects of prolonged wakefulness on vigilant attention and the sleep EEG.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Attention / drug effects
  • Benzhydryl Compounds / pharmacology
  • Caffeine / pharmacology*
  • Central Nervous System Stimulants / pharmacology*
  • Cross-Over Studies
  • Double-Blind Method
  • Electroencephalography
  • Female
  • Humans
  • Male
  • Middle Aged
  • Modafinil
  • Polymorphism, Single Nucleotide
  • Psychomotor Performance / drug effects
  • Purinergic P1 Receptor Antagonists / pharmacology*
  • Receptor, Adenosine A2A / genetics*
  • Sleep Deprivation / genetics*
  • Sleep Deprivation / physiopathology
  • Wakefulness / drug effects
  • Young Adult


  • Benzhydryl Compounds
  • Central Nervous System Stimulants
  • Purinergic P1 Receptor Antagonists
  • Receptor, Adenosine A2A
  • Caffeine
  • Modafinil