Abstract
The ability of nicotine to alter firing of dopamine neurons is the first step leading to nicotine reward, but activation of intracellular signaling pathways downstream of nicotinic acetylcholine receptors is likely to be critical for longer-term consequences of nicotine exposure, including conditioned reward. The transcription factor cyclic AMP-response element binding protein (CREB) is important for new gene transcription and in its phosphorylated form (pCREB) promotes long-term changes in synaptic strength. Previous studies have implicated nucleus accumbens (NAc) CREB activity in the modulation of cocaine and morphine reward, and have shown that nicotine conditioned place preference (CPP) is associated with NAc CREB activation. It is not clear whether CPP elicits phosphorylation of CREB or if elevations in pCREB support nicotine CPP. In the current study, we investigated levels of CREB and pCREB during Pavlovian conditioning with nicotine in a novel context in the absence of chamber choice. Nicotine context conditioning resulted in elevated pCREB levels in the NAc shell but not the NAc core of mice following placement in the nicotine-paired chamber in the absence of nicotine. To test if CREB activity in the NAc shell contributes to cue-induced responses that may precipitate nicotine-seeking, we used viral-mediated gene transfer of a dominant-negative CREB construct in the NAc shell of C57BL/6J mice and found that disruption of CREB activation before training blocked nicotine place preference across a range of doses. Taken together, these studies identify the NAc shell as a brain region where CREB activity is essential for nicotine CPP.
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Acknowledgements
We thank J Chang, C Kochevar, Y Pham, B Schneider and C Wein for technical assistance, and William A Carlezon for thoughtful comments on this paper. This work was supported by National Institutes of Health grants AA15632, DA14241, DA10455, a Lieber NARSAD Young Investigator Award to DHB, and DA00436 to MRP. We especially thank Constance and Steven Lieber for their generous support of this work through NARSAD.
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The authors have no financial conflicts of interest with any data or original ideas presented in this paper. DH Brunzell and RL Neve are supported by the National Institute of Health (NIH) for projects unrelated to the work presented in this paper. YS Mineur is supported by the National Institute of Health and by a Pfizer contract for an unrelated project. In addition to the NIH support of this work and other projects, MR Picciotto has received funding from Pfizer for unrelated research endeavors. YS Mineur and MR Picciotto have a patent on cytisine derivatives as novel treatments for depression.
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Brunzell, D., Mineur, Y., Neve, R. et al. Nucleus Accumbens CREB Activity is Necessary for Nicotine Conditioned Place Preference. Neuropsychopharmacol 34, 1993–2001 (2009). https://doi.org/10.1038/npp.2009.11
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DOI: https://doi.org/10.1038/npp.2009.11
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