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CELLULAR AND MOLECULAR

Nicotine and Ethanol Activate Protein Kinase A Synergistically via G_i Subunits in Nucleus Accumbens/Ventral Tegmental Cocultures: The Role of Dopamine D₁/D₂ and Adenosine A_2A Receptors

Department of Neurology, Ernest Gallo Clinic and Research Center, University of California, San Francisco, California (Y.I., F.W.H., A.B.); and CV Therapeutics, Palo Alto, California (L.Y., P.F., Z.J., I.D.)

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 A_2A receptor antagonists, G 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 A_2A receptors. These data provide a novel cellular mechanism, involving G subunits, A_2A 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.

Address correspondence to: Ivan Diamond, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA 94304. E-mail: ivan.diamond{at}cvt.com