Acute nicotine-induced tachyphylaxis is differentially manifest in the limbic system.


Journal Article

Rapid tolerance develops to many of nicotine's behavioral and autonomic effects. A better understanding of the spatiotemporal patterns in neuronal activity as a consequence of acute nicotine tolerance (tachyphylaxis) may help explain its commonly found inverted 'U'-shaped biphasic dose-effect relationship on various behaviors. To this end, we employed high-resolution functional magnetic resonance imaging and relative cerebral blood volume (rCBV) as a marker of neuronal activity, to characterize the regional development of acute tolerance as a function of nicotine dose in naïve, anesthetized rats. A single intravenous nicotine injection at 0.1 and 0.3, but not 0.03 mg/kg, significantly increased neuronal activity in many neocortical areas. In contrast, dose-dependent increases in rCBV were most pronounced in limbic regions, such that responses seen at 0.1 mg/kg nicotine in accumbens, hippocampus, amygdala, and several other limbic areas were not seen following 0.3 mg/kg nicotine. Finally, whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, subcortical limbic structures showed only a weak trend for tolerance. Lack of rCBV changes in animals receiving nicotine methiodide, a quaternary nicotine analog that does not cross the blood-brain barrier, supports a direct neuronal effect of nicotine rather than an action on the vasculature. These data provide pharmacodynamic insight into the regional heterogeneity of nicotine tachyphylaxis development, which may be relevant to behavioral and neurobiological mechanisms associated with repeated tobacco consumption.

Full Text

Cited Authors

  • Zuo, Y; Lu, H; Vaupel, DB; Zhang, Y; Chefer, SI; Rea, WR; Moore, AV; Yang, Y; Stein, EA

Published Date

  • November 2011

Published In

Volume / Issue

  • 36 / 12

Start / End Page

  • 2498 - 2512

PubMed ID

  • 21796109

Pubmed Central ID

  • 21796109

Electronic International Standard Serial Number (EISSN)

  • 1740-634X

International Standard Serial Number (ISSN)

  • 0893-133X

Digital Object Identifier (DOI)

  • 10.1038/npp.2011.139


  • eng