Nicotine and ethanol cooperate to enhance ventral tegmental area AMPA receptor function via α6-containing nicotinic receptors

NEUROPHARMACOLOGY

卷:91

Article

Engle, Staci E.¹  McIntosh, J. Michael^2,3,4  Drenan, Ryan M.¹ 

[1] Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA

[2] George E Wahlen Vet Affairs Med Ctr, Salt Lake City, UT 84148 USA

[3] Univ Utah, Dept Psychiat, Salt Lake City, UT 84148 USA

[4] Univ Utah, Dept Biol, Salt Lake City, UT 84148 USA

关键词: Nicotine;    Alcohol;    Addiction;    Dopamine;    Glutamate;    Co-exposure;   

DOI  :  10.1016/j.neuropharm.2014.11.014

来源: Elsevier

【 摘 要 】

Nicotine + ethanol co-exposure results in additive and/or synergistic effects in the ventral tegmental area (VTA) to nucleus accumbens (NAc) dopamine (DA) pathway, but the mechanisms supporting this are unclear. We tested the hypothesis that nAChRs containing alpha 6 subunits (alpha 6* nAChRs) are involved in the response to nicotine + ethanol co-exposure. Exposing VTA slices from C57BL/6 WT animals to drinking-relevant concentrations of ethanol causes a marked enhancement of alpha-amino-3-hydroxy-5-methylisoxazolepropionic acid (AMPA) receptor (AMPAR) function in VTA neurons. This effect was sensitive to a-conotoxin MII (an alpha 6 beta 2* nAChR antagonist), suggesting that alpha 6* nAChR function is required. In mice expressing hypersensitive alpha 6* nAChRs (alpha 6L9S mice), we found that lower concentrations (relative to C57BL/6 WT) of ethanol were sufficient to enhance AMPAR function in VTA neurons. Exposure of live C57BL/6 WT mice to ethanol also produced AMPAR functional enhancement in VTA neurons, and studies in alpha 6L9S mice strongly suggest a role for alpha 6* nAChRs in this response. We then asked whether nicotine and ethanol cooperate to enhance VTA AMPAR function. We identified low concentrations of nicotine and ethanol that were capable of strongly enhancing VTA AMPAR function when co-applied to slices, but that did not enhance AMPAR function when applied alone. This effect was sensitive to both varenicline (an alpha 4 beta 2* and alpha 6 beta 2* nAChR partial agonist) and alpha-conotoxin MII Finally, nicotine + ethanol co-exposure also enhanced AMPAR function in VTA neurons from alpha 6L9S mice. Together, these data identify alpha 6* nAChRs as important players in the response to nicotine + ethanol co-exposure in VTA neurons. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

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