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 journalArticle

1 Citation (Scopus)

Abstract

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
JournalPsychopharmacology
Volume221
Issue number4
DOIs
StatePublished - Jun 2012
Externally publishedYes

Fingerprint

Self Administration
Nicotine
Dopamine Plasma Membrane Transport Proteins
Cytochrome P-450 Enzyme System
Operant Conditioning
Harm Reduction
Cotinine
Nicotinic Receptors

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Substituted heteroaromatic compounds : Effect on nicotine self-administration in rats. / Cashman, John R.; Okolotowicz, Karl; Cerny, Matt; Johnson, Robert; Janowsky, Aaron; Azar, Marc R.

In: Psychopharmacology, Vol. 221, No. 4, 06.2012, p. 637-648.

Research output: Contribution to journalArticle

Cashman, John R. ; Okolotowicz, Karl ; Cerny, Matt ; Johnson, Robert ; Janowsky, Aaron ; Azar, Marc R. / Substituted heteroaromatic compounds : Effect on nicotine self-administration in rats. In: Psychopharmacology. 2012 ; Vol. 221, No. 4. pp. 637-648.
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