Theobromine Up-Regulates Cerebral Brain-Derived Neurotrophic Factor and Facilitates Motor Learning in Mice

J Nutr Biochem. 2017 Jan;39:110-116. doi: 10.1016/j.jnutbio.2016.10.002. Epub 2016 Oct 8.


Theobromine, which is a caffeine derivative, is the primary methylxanthine produced by Theobroma cacao. Theobromine works as a phosphodiesterase (PDE) inhibitor to increase intracellular cyclic adenosine monophosphate (cAMP). cAMP activates the cAMP-response element-binding protein (CREB), which is involved in a large variety of brain processes, including the induction of the brain-derived neurotrophic factor (BDNF). BDNF supports cell survival and neuronal functions, including learning and memory. Thus, cAMP/CREB/BDNF pathways play an important role in learning and memory. Here, we investigated whether orally administered theobromine could act as a PDE inhibitor centrally and affect cAMP/CREB/BDNF pathways and learning behavior in mice. The mice were divided into two groups. The control group (CN) was fed a normal diet, whereas the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 30 days. We measured the levels of theobromine, phosphorylated vasodilator-stimulated phosphoprotein (p-VASP), phosphorylated CREB (p-CREB), and BDNF in the brain. p-VASP was used as an index of cAMP increases. Moreover, we analyzed the performance of the mice on a three-lever motor learning task. Theobromine was detectable in the brains of TB mice. The brain levels of p-VASP, p-CREB, and BDNF were higher in the TB mice compared with those in the CN mice. In addition, the TB mice performed better on the three-lever task than the CN mice did. These results strongly suggested that orally administered theobromine acted as a PDE inhibitor in the brain, and it augmented the cAMP/CREB/BDNF pathways and motor learning in mice.

Keywords: BDNF; CREB phosphorylation; Motor learning; Phosphodiesterase; VASP phosphorylation; cAMP.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cacao / chemistry
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cyclic AMP / genetics
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Learning*
  • Male
  • Memory
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Plant Extracts / pharmacology
  • Theobromine / blood
  • Theobromine / pharmacology*
  • Up-Regulation


  • Blood Glucose
  • Brain-Derived Neurotrophic Factor
  • Cell Adhesion Molecules
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Microfilament Proteins
  • Phosphodiesterase Inhibitors
  • Phosphoproteins
  • Plant Extracts
  • vasodilator-stimulated phosphoprotein
  • BDNF protein, human
  • Cyclic AMP
  • Theobromine