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.
Footnotes
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This work was supported by funds provided by the State of California for Medical Research on Alcohol and Substance Abuse through the University of California, San Francisco (to A.B.) and by the Department of the Army (Grant DAMD17-03-1-0061) (to I.D.). The United States Army Medical Research Acquisition Activity, 820 Chandler Street, Fort Detrick, MD 21702-5014 is the awarding and administering acquisition office. The content of the information represented does not necessarily reflect the position or the policy of the United States Government, and no official endorsement should be inferred.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.120675.
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ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; A2AR, adenosine 2A receptor; MSN, medium spiny neuron; D1R, dopamine D1 receptor; D2R, dopamine D2 receptor; GAD, glutamic acid decarboxylase; NAcb, nucleus accumbens; CRE, cAMP-response element; PBS, phosphate-buffered saline; PKA, protein kinase A; SCH23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride; eticlopride, S-(–)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamide hydrochloride; H-89, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide dihydrochloride; MSX-3, 3,7-dihydro-8-[(1E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-3-[3-(phosphonooxy)]-5-[propyl-1-(2-propynyl)]-1H-purine-2,6-dione disodium salt hydrate; FITC, fluorescein isothiocyanate; TH, tyrosine hydroxylase; VTA, ventral tegmental area; Luc, luciferase; βARK, β-adrenergic receptor kinase.
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↵1 Current affiliation: Department of Psychiatry, Nara Medical University, Kashihara, Nara, Japan.
- Received February 5, 2007.
- Accepted April 25, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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