Substituted heteroaromatic compounds: Effect on nicotine self-administration in rats

John R. Cashman, Karl Okolotowicz, Matt Cerny, Robert Johnson, Aaron Janowsky, Marc R. Azar

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Rationale: Certain compounds that nonselectively inhibit a prominent human nicotine-metabolizing enzyme (i.e., human cytochrome P-450 2A6, hCYP 2A6) showed inhibition of smoking in humans. However, a comprehensive examination of hCYP 2A6 inhibitors to decrease nicotine self-administration in rats has not been reported. Objectives: We tested substituted heteroaromatic compounds designed to selectively inhibit hCYP 2A6 in a model system to (a) examine selective hCYP 2A6 inhibitors to decrease cotinine formation in vivo in rats administered with nicotine and (b) examine their efficacy to decrease nicotine self-administration in rats. Methods: Rats were trained to IV self-administer nicotine in 1-h sessions. Nicotine self-administration was carried out at a unit dose of 0.03 mg/kg/infusion in 0.1 ml/s. Pretreatment with substituted heteroaromatic test compounds (0.5-25 mg/kg, i.p., 30 min prior to nicotine self-administration sessions) resulted in dose-dependent decreases of nicotine self-administration. Using operant conditioning techniques, nicotine- vs. food-reinforced responding was evaluated for compounds 10 and 11. Results: Compounds 10 and 11 selectively decreased nicotine self-administration with estimated ED 50 values 4 and 2.8 mg/kg, respectively. Of the test compounds examined, none showed significant affinity for mammalian α4β2- or α7-neuronal nicotinic acetylcholine (nAChR) receptors and none were inhibitors of the human dopamine transporter (hDAT); thus, neither the endogenous nAChRs nor DAT apparently plays a role in decreasing nicotine self-administration for this series of compounds. Conclusion: The results indicate that chemical analogs of nicotine can play a role in nicotine self-administration harm reduction but a non-nAChR and a non-hDAT mechanism are likely involved.

Original languageEnglish (US)
Pages (from-to)637-648
Number of pages12
Issue number4
StatePublished - Jun 2012
Externally publishedYes


  • Cytochrome P-450 2A6
  • Dopamine transporter
  • Neuronal nicotinic acetylcholine receptors
  • Nicotine metabolism
  • Nicotine self-administration

ASJC Scopus subject areas

  • Pharmacology


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