Anatomy of adenosine A2A receptors in brain: morphological substrates for integration of striatal function

Neurology. 2003 Dec 9;61(11 Suppl 6):S12-8. doi: 10.1212/01.wnl.0000095205.33940.99.


A2A adenosine receptors (A(2A)Rs) are expressed with the greatest abundance in the striatum and other nuclei of the basal ganglia. The segregated expression of A(2A)Rs on the GABAergic striatopallidal medium spiny neurons, where A(2A)R and D2 dopamine receptor mRNAs are colocalized, and the opposing functional interaction between adenosine and dopamine suggest that A(2A)Rs may be an important therapeutic target. To further explore the role of A(2A)Rs in the synaptic organization of the basal ganglia, the authors developed an antibody directed against the purified A(2A)R. Immunohistochemical studies in rat brain showed dense labeling of the neuropil in the striatum, nucleus accumbens, and olfactory tubercles with lighter labeling of terminals in the globus pallidus (GP), where A(2A)R transcript is not detected. Stimulation of A(2A)Rs on GP terminals may facilitate GABAergic signaling and contribute to the overactivation observed in Parkinson's disease (PD). Analysis at the ultrastructural level allowed a more detailed characterization of the mechanism(s) of A2A-mediated control of striatal output. In the striatum, terminals expressing A(2A)Rs accounted for 25% of the labeled elements. These presynaptic receptors may facilitate excitatory glutamatergic, inhibitory GABAergic, and possibly cholinergic striatal transmission. However, the majority of striatal A(2A)R immunoreactivity was found on postsynaptic elements, including dendrites of striatopallidal neurons, in which A(2A)R and GABA immunoreactivity is colocalized. Activation of these receptors may promote GABAergic signaling in striatopallidal output neurons and their local axon collaterals in the striatum. Many of the A2A-labeled dendrites were contacted by terminals forming asymmetric (excitatory) possibly glutamatergic synapses. Using the vesicular glutamate transporters (VGLUTs) as markers of glutamatergic terminals, the authors have found that VGLUT1-immunoreactive (ir) terminals make asymmetric contacts on A2A-ir spines and spine heads in the striatum, suggesting that regulation of striatal output by A(2A)R stimulation may involve facilitation of the cortical glutamatergic excitatory input to striatopallidal neurons. These ultrastructural findings suggest several pathways through which A2A receptor blockade may act to dampen the elevated striatopallidal GABAergic signaling that occurs in PD.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Basal Ganglia / anatomy & histology
  • Basal Ganglia / metabolism
  • Brain / anatomy & histology*
  • Brain / metabolism
  • Corpus Striatum / anatomy & histology
  • Corpus Striatum / metabolism
  • Dendrites / metabolism
  • Dendrites / ultrastructure
  • Humans
  • Neurons / metabolism
  • Neurons / ultrastructure
  • Receptor, Adenosine A2A / biosynthesis*


  • Receptor, Adenosine A2A