Reward sensitization: Effects of repeated nicotine exposure and withdrawal in mice

Monica R.F. Hilario, Jill R. Turner, Julie A. Blendy

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Tobacco dependence is an addiction with high rates of relapse, resulting in multiple quit attempts in individuals who are trying to stop smoking. How these multiple cycles of smoking and withdrawal contribute to nicotine dependence, long-term alterations in brain reward systems, and nicotine receptor regulation is unknown. Therefore, to evaluate how multiple exposures of nicotine and withdrawal periods modulate rewarding properties of nicotine, we used intracranial self-stimulation to measure alterations in the threshold of brain stimulation reward. In addition, we employed the conditioned place preference (CPP) paradigm to evaluate positive context conditioning following each withdrawal period and measured levels of neuronal nicotinic receptors in cortex, striatum, and hippocampus. We found that repeated nicotine exposure and withdrawal enhanced brain stimulation reward and reward sensitivity to acute injections of nicotine. This increased reward was reflected by enhanced CPP to nicotine. Chronic nicotine is known to up-regulate nAChRs (nicotinic acetylcholine receptors) and we found that this up-regulation was maintained for up to 8 days of withdrawal in the striatum and in the hippocampus, but not in the cortex, of animals exposed to multiple nicotine exposure and withdrawal periods. These results demonstrate that repeated exposures to nicotine, followed by withdrawal, induce a persistent increase in both brain reward function and sensitivity to the hedonic value of nicotine and long-lasting up-regulation of neuronal nicotinic receptors. Together, these data suggest that a continuing increase in brain reward function and enhanced sensitivity to nicotine reward following repeated withdrawal periods may be one reason why smokers relapse frequently.

Original languageEnglish
Pages (from-to)2661-2670
Number of pages10
Issue number12
StatePublished - Nov 2012

Bibliographical note

Funding Information:
We thank Stephen Mague and Luis Tuesta for support with ICSS protocols. This research was supported by Grants T32-DA028874 (MRFH) and P50-CA-02585-01 (JAB).


  • ICSS
  • addiction
  • model
  • mouse
  • nicotine
  • withdrawal

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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