TY - JOUR
T1 - Substituted heteroaromatic compounds
T2 - Effect on nicotine self-administration in rats
AU - Cashman, John R.
AU - Okolotowicz, Karl
AU - Cerny, Matt
AU - Johnson, Robert
AU - Janowsky, Aaron
AU - Azar, Marc R.
N1 - Funding Information:
Acknowledgments We thank Dr. Senait Ghirmai for the synthesis of compound 2 and Dr. Travis Denton for the synthesis of compound 5 and for the pharamacokinetic studies (Table 6). This work was supported by funds from HBRI.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - Cytochrome P-450 2A6
KW - Dopamine transporter
KW - Neuronal nicotinic acetylcholine receptors
KW - Nicotine metabolism
KW - Nicotine self-administration
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U2 - 10.1007/s00213-011-2608-6
DO - 10.1007/s00213-011-2608-6
M3 - Article
C2 - 22218454
AN - SCOPUS:84862691418
SN - 0033-3158
VL - 221
SP - 637
EP - 648
JO - Psychopharmacology
JF - Psychopharmacology
IS - 4
ER -