Adenosine receptor antagonists including caffeine alter fetal brain development in mice

Sci Transl Med. 2013 Aug 7;5(197):197ra104. doi: 10.1126/scitranslmed.3006258.


Consumption of certain substances during pregnancy can interfere with brain development, leading to deleterious long-term neurological and cognitive impairments in offspring. To test whether modulators of adenosine receptors affect neural development, we exposed mouse dams to a subtype-selective adenosine type 2A receptor (A2AR) antagonist or to caffeine, a naturally occurring adenosine receptor antagonist, during pregnancy and lactation. We observed delayed migration and insertion of γ-aminobutyric acid (GABA) neurons into the hippocampal circuitry during the first postnatal week in offspring of dams treated with the A2AR antagonist or caffeine. This was associated with increased neuronal network excitability and increased susceptibility to seizures in response to a seizure-inducing agent. Adult offspring of mouse dams exposed to A2AR antagonists during pregnancy and lactation displayed loss of hippocampal GABA neurons and some cognitive deficits. These results demonstrate that exposure to A2AR antagonists including caffeine during pregnancy and lactation in rodents may have adverse effects on the neural development of their offspring.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Animals
  • Animals, Newborn
  • Brain / drug effects*
  • Brain / embryology*
  • Brain / pathology
  • Caffeine / pharmacology*
  • Cell Movement / drug effects
  • Cognition Disorders / pathology
  • Disease Susceptibility
  • Female
  • Fetus / drug effects*
  • Fetus / embryology*
  • Fetus / pathology
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism
  • Glutamates / metabolism
  • Green Fluorescent Proteins / metabolism
  • Haplorhini / embryology
  • Hippocampus / drug effects
  • Hippocampus / embryology
  • Hippocampus / pathology
  • Mice
  • Nerve Net / drug effects
  • Pregnancy
  • Purinergic P1 Receptor Antagonists / pharmacology*
  • Rats
  • Receptors, Adenosine A2 / metabolism
  • Seizures / embryology
  • Seizures / pathology
  • Telencephalon / drug effects
  • Telencephalon / embryology
  • Telencephalon / pathology


  • Glutamates
  • Purinergic P1 Receptor Antagonists
  • Receptors, Adenosine A2
  • Green Fluorescent Proteins
  • Caffeine