Adenosine A2a blockade prevents synergy between mu-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats

Proc Natl Acad Sci U S A. 2006 May 16;103(20):7877-82. doi: 10.1073/pnas.0602661103. Epub 2006 May 9.


Relapse is the most serious limitation of effective medical treatment of opiate addiction. Opiate-related behaviors appear to be modulated by cannabinoid CB1 receptors (CB1) through poorly understood cross-talk mechanisms. Opiate and CB1 receptors are coexpressed in the nucleus accumbens (NAc) and dorsal striatum. These regions also have the highest density of adenosine A2a receptors (A2a) in the brain. We have been investigating the postsynaptic signaling mechanisms of mu-opiate receptors (MORs) and CB1 receptors in primary NAc/striatal neurons. In this article, we present evidence that MOR and CB1 act synergistically on cAMP/PKA signaling in NAc/striatal neurons. In addition, we find that synergy requires adenosine and A2a. Importantly, an A2a antagonist administered either directly into the NAc or indirectly by i.p. injection eliminates heroin-induced reinstatement in rats trained to self-administer heroin, a model of human craving and relapse. These findings suggest that A2a antagonists might be effective therapeutic agents in the management of abstinent heroin addicts.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine A2 Receptor Antagonists
  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacology
  • Animals
  • Arachidonic Acids / metabolism
  • Arachidonic Acids / pharmacology
  • Behavior, Animal / drug effects
  • Behavior, Animal / physiology*
  • Corpus Striatum / cytology
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Drug Synergism*
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / metabolism
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enzyme Activation
  • Gene Expression Regulation / drug effects
  • Heroin Dependence*
  • Humans
  • Male
  • Neurons / drug effects
  • Neurons / metabolism
  • Nucleus Accumbens / cytology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Adenosine A2A* / metabolism
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptors, Opioid, mu / metabolism*
  • Self Administration
  • Signal Transduction / physiology*
  • Theobromine / analogs & derivatives
  • Theobromine / metabolism
  • Theobromine / pharmacology
  • Xanthines / metabolism
  • Xanthines / pharmacology


  • Adenosine A2 Receptor Antagonists
  • Analgesics, Opioid
  • Arachidonic Acids
  • Receptor, Adenosine A2A
  • Receptor, Cannabinoid, CB1
  • Receptors, Opioid, mu
  • Xanthines
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • methanandamide
  • 3,7-dimethyl-1-propargylxanthine
  • 1,3-dipropyl-8-cyclopentylxanthine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Theobromine