@article {Inoue23, author = {Yuichiro Inoue and Lina Yao and F. Woodward Hopf and Peidong Fan and Zhan Jiang and Antonello Bonci and Ivan Diamond}, title = {Nicotine and Ethanol Activate Protein Kinase A Synergistically via Gi βγ Subunits in Nucleus Accumbens/Ventral Tegmental Cocultures: The Role of Dopamine D1/D2 and Adenosine A2A Receptors}, volume = {322}, number = {1}, pages = {23--29}, year = {2007}, doi = {10.1124/jpet.107.120675}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Tobacco and alcohol are the most commonly used drugs of abuse and show the most serious comorbidity. The mesolimbic dopamine system contributes significantly to nicotine and ethanol reinforcement, but the underlying cellular signaling mechanisms are poorly understood. Nicotinic acetylcholine (nACh) receptors are highly expressed on ventral tegmental area (VTA) dopamine neurons, with relatively low expression in nucleus accumbens (NAcb) neurons. Because dopamine receptors D1 and D2 are highly expressed on NAcb neurons, nicotine could influence NAcb neurons indirectly by activating VTA neurons to release dopamine in the NAcb. To investigate this possibility in vitro, we established primary cultures containing neurons from VTA or NAcb separately or in cocultures. Nicotine increased cAMP response element-mediated gene expression only in cocultures; this increase was blocked by nACh or dopamine D1 or D2 receptor antagonists. Furthermore, subthreshold concentrations of nicotine with ethanol increased gene expression in cocultures, and this increase was blocked by nACh, D2 or adenosine A2A receptor antagonists, Gβγ or protein kinase A (PKA) inhibitors, and adenosine deaminase. These results suggest that nicotine activated VTA neurons, causing the release of dopamine, which in turn stimulated both D1 and D2 receptors on NAcb neurons. In addition, subthreshold concentrations of nicotine and ethanol in combination also activated NAcb neurons through synergy between D2 and A2A receptors. These data provide a novel cellular mechanism, involving Gβγ subunits, A2A receptors, and PKA, whereby combined use of tobacco and alcohol could enhance the reinforcing effect in humans as well as facilitate long-term neuroadaptations, increasing the risk for developing coaddiction. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/322/1/23}, eprint = {https://jpet.aspetjournals.org/content/322/1/23.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }