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. 2006 May 16;103(20):7877-82.
doi: 10.1073/pnas.0602661103. Epub 2006 May 9.

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

Lina Yao  1 , Krista McFarland, Peidong Fan, Zhan Jiang, Takashi Ueda, Ivan Diamond
Affiliations

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

Lina Yao et al. Proc Natl Acad Sci U S A. .

Abstract

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.

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Conflict of interest statement

Conflict of interest statement: A patent application concerning this work is under review and will be owned by the University of California at San Francisco. I.D. is Vice President and L.Y. is a Senior Scientist at CV Therapeutics, Inc.

Figures

Fig. 1.
Fig. 1.
CB1 preferentially interacts with Gαi3 in NAc/striatal neurons. Coimmunoprecipitation of CB1 with Gαi3 subunits. CB1 was immunoprecipitated with specific polyclonal anti-CB1 antibodies and probed with anti-Gαo, Gαi1, Gαi2, or Gαi3 antibodies. The blot shown is representative of three separate experiments.
Fig. 2.
Fig. 2.
DAMGO and Met act synergistically to induce CRE-mediated gene expression in primary NAc/striatal neurons. (A) Cells were transfected with HSVCRE-Luc and treated with 0.01 nM DAMGO (DAM) or 0.02 nM Met alone or in combination for 10 min. Cells were then washed and cultured for 5 h before luciferase assay. (B) Cells were treated as above, with various concentrations of Met plus 0.01 nM DAMGO for 10 min. Luciferase was assayed as above. (C) Cells were treated with various concentrations of DAMGO plus 0.02 nM Met. The EC50 value was calculated by using GraphPad prism software. ∗, P < 0.01 compared with control (one-way ANOVA and Dunnett’s test).
Fig. 3.
Fig. 3.
Synergy requires adenosine A2a activation. Cells were cultured, treated, and assayed for luciferase activity as in Fig. 2A. Where indicated, cells were preincubated with 1 unit/ml adenosine deaminase (ADA), DMPX (10 μM), MSX-3 (100 nM), or DPCPX (100 nM) for 30 min. Data are the mean ± SE of three experiments. ∗, P < 0.01 compared with control (one-way ANOVA and Dunnett’s test).
Fig. 4.
Fig. 4.
A2a antagonists eliminate heroin-seeking behavior in rats. (A) DMPX in NAc inhibition of heroin reinstatement. DMPX (5 nmol) or DPCPX (5 nmol) was infused into the NAc. (B) MSX-3 (3 mg/kg) was injected i.p. DMPX (pretreatment time, 25 min) in NAc and MSX-3 i.p. each prevented reinstatement of lever-pressing elicited by a priming injection of heroin (0.25 mg/kg, s.c.). Inactive lever-press responses were not different across drug treatment conditions. Data represent mean active lever presses ± SEM (n = 8 in all groups). ∗, P < 0.01 compared with extinction responding (two-way ANOVA and Tukey’s posttest).
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