NDLI: Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-βγ dimers

Content Provider	PubMed Central
Author	Yao, Lina Fan, Peidong Jiang, Zhan Mailliard, William S. Gordon, Adrienne S. Diamond, Ivan
Copyright Year	2003
Abstract	The mesolimbic dopamine system and cAMP-dependent/protein kinase A (PKA) pathways are strongly implicated in addictive behaviors. Here we determine the role of dopamine D2 receptors (D2) in PKA signaling responses to δ-opioid (DOR) and cannabinoid (CB1) receptors. We find in NG108-15/D2 cells and in cultured primary neurons that a brief exposure to saturating concentrations of DOR and CB1 agonists increases cAMP, promotes PKA Cα translocation and increases cAMP-dependent gene expression. Activation of PKA signaling is mediated by Gi-βγ dimers. Importantly, subthreshold concentrations of DOR or CB1 agonists with D2 agonists, which are without effect when added separately, together activate cAMP/PKA signaling synergistically. There is also synergy between DOR or CB1 with ethanol, another addicting agent. In all instances, synergy requires adenosine activation of adenosine A2 receptors and is mediated by βγ dimers. Synergy by this molecular mechanism appears to confer hypersensitivity to opioids and cannabinoids while simultaneously increasing the sensitivity of D2 signaling when receptors are expressed on the same cells. This mechanism may account, in part, for drug-induced activation of medium spiny neurons in the nucleus accumbens.
Related Links	http://dx.doi.org/10.1073/pnas.2336093100
Ending Page	14384
Page Count	6
Starting Page	14379
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	24
Volume Number	100
Language	English
Publisher	National Academy of Sciences
Publisher Date	2003-11-25
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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