, 207:57

Nicotine-conditioned place preference induced CREB phosphorylation and Fos expression in the adult rat brain

  • Mariano M. Pascual
  • Veronica Pastor
  • Ramon O. Bernabeu
Original Investigation



Experimental evidence indicates that nicotine causes long-lasting changes in the brain associated with behavior. Although much has been learned about factors participating in this process, less is known concerning the mechanisms and brain areas involved in nicotine preference.


The objective of this study is to examine the participation of brain structures during the development of nicotine-conditioned place preference (CPP).


To identify brain regions activated in CPP, we have measured the levels of phosphorylated cyclic AMP response element binding protein (pCREB) and Fos protein using a behavioral CPP and conditioned place aversion (CPA) paradigms.


Rats developed reliable and robust CPP and also CPA. During nicotine preference and reinstatement behaviors, a significant increase of both pCREB and Fos protein expression occurs in the nucleus accumbens (NAc) and ventral tegmental area (VTA) and also in the prefrontal cortex (PFC), dorsal striatum (DStr), amygdala, and hippocampus. These increases were abolished by the administration of mecamylamine or by a CPA protocol, showing a specific activation of pCREB in drug preference animals, mediated by nicotinic receptors. Specifically in the VTA, nicotine-induced preference and reinstatement of the preference caused the activation of dopaminergic and GABAergic cells in different proportions.


The results indicate that the phosphorylation of CREB and expression of Fos protein, as indicators of neural activity, accompany the acquisition and maintenance of nicotine-induced CPP but not CPA in mesolimbic areas (NAc, VTA, PFC, and DStr) as well as in memory consolidation structures (hippocampus and amygdala) and nicotinic receptor are involved in this process. Taken together, these studies identify the brain regions where pCREB activity is essential for nicotine preference.


Nicotine VTA c-fos Prefrontal cortex CREB Immunohistochemistry Withdrawal Nucleus accumbens Place conditioning 

Supplementary material

213_2009_1630_Fig11_ESM.gif (47 kb)
Figure 1Sa Low magnification pictures shows the brain areas analyzed for VTA and NAc. NAcc NAc core, NAcs NAc shell. b The stringent criterion applied to pCREB and Fos quantification. a The picture shows pCREB-positive nuclei and a line used as a reference to measure the intensity of each nucleus, named 1, 2, 3, and 4. Scale bar 20 µm. b The y-axis represents intensity. The x-axis represents the distance of the line drew in a. Each number represents the four nucleus of figure a. Only the intensity values that were higher than a determined intensity (horizontal arrow) were considered positive (GIF 47.3 kb)
213_2009_1630_MOESM1_ESM.tif (2.5 mb)
High resolution image file (TIFF 2.52 mb)

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Mariano M. Pascual
    • 1
  • Veronica Pastor
    • 1
  • Ramon O. Bernabeu
    • 1
  1. 1.Department of Physiology and Institute of Cell Biology, School of MedicineUniversity of Buenos AiresBuenos AiresArgentina

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