Overexpression of CRF in the BNST diminishes dysphoria but not anxiety-like behavior in nicotine withdrawing rats

Eur Neuropsychopharmacol. 2016 Sep;26(9):1378-1389. doi: 10.1016/j.euroneuro.2016.07.007. Epub 2016 Jul 22.


Smoking cessation leads to dysphoria and anxiety, which both increase the risk for relapse. This negative affective state is partly mediated by an increase in activity in brain stress systems. Recent studies indicate that prolonged viral vector-mediated overexpression of stress peptides diminishes stress sensitivity. Here we investigated whether the overexpression of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST) diminishes nicotine withdrawal symptoms in rats. The effect of nicotine withdrawal on brain reward function was investigated with an intracranial self-stimulation (ICSS) procedure. Anxiety-like behavior was investigated in the elevated plus maze test and a large open field. An adeno-associated virus (AAV) pseudotype 2/5 vector was used to overexpress CRF in the lateral BNST and nicotine dependence was induced using minipumps. Administration of the nicotinic receptor antagonist mecamylamine and cessation of nicotine administration led to a dysphoria-like state, which was prevented by the overexpression of CRF in the BNST. Nicotine withdrawal also increased anxiety-like behavior in the elevated plus maze test and large open field test and slightly decreased locomotor activity in the open field. The overexpression of CRF in the BNST did not prevent the increase in anxiety-like behavior or decrease in locomotor activity. The overexpression of CRF increased CRF1 and CRF2 receptor gene expression and increased the CRF2/CRF1 receptor ratio. In conclusion, the overexpression of CRF in the BNST prevents the dysphoria-like state associated with nicotine withdrawal and increases the CRF2/CRF1 receptor ratio, which may diminish the negative effects of CRF on mood.

Keywords: AAV vectors; CRF; Dependence; Dysphoria; Nicotine; Overexpression.

MeSH terms

  • Animals
  • Anxiety / metabolism
  • Corticotropin-Releasing Hormone / genetics
  • Corticotropin-Releasing Hormone / metabolism*
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Vectors
  • Male
  • Mecamylamine / pharmacology
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Nicotine / toxicity
  • Nicotinic Agonists / toxicity
  • Nicotinic Antagonists / pharmacology
  • Rats, Wistar
  • Receptors, Corticotropin-Releasing Hormone / metabolism
  • Receptors, Nicotinic / metabolism
  • Reward*
  • Self Stimulation
  • Septal Nuclei / drug effects
  • Septal Nuclei / metabolism*
  • Substance Withdrawal Syndrome / metabolism*
  • Substance Withdrawal Syndrome / prevention & control
  • Substance Withdrawal Syndrome / psychology*
  • Tobacco Use Disorder / metabolism*
  • Tobacco Use Disorder / psychology


  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, Nicotinic
  • Mecamylamine
  • Nicotine
  • Corticotropin-Releasing Hormone