Tags

Type your tag names separated by a space and hit enter

The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice.
Psychopharmacology (Berl). 2017 Mar; 234(5):781-792.P

Abstract

RATIONALE

The extent to which non-α4β2 versus α4β2* nAChRs contribute to the behavioral effects of varenicline and other nAChR agonists is unclear.

OBJECTIVES

The purpose of this study was to characterize the discriminative stimulus effects of varenicline and nicotine using various nAChR agonists and antagonists to elucidate possible non-α4β2 nAChR mechanisms.

METHODS

Separate groups of male C57BL/6J mice were trained to discriminate varenicline (3.2 mg/kg) or nicotine (1 mg/kg). Test drugs included mecamylamine; the nAChR agonists epibatidine, nicotine, cytisine, varenicline, and RTI-102; the β2-containing nAChR antagonist dihydro-β-erythroidine (DHβE); the α7 nAChR agonist PNU-282987; the α7 antagonist methyllycaconitine (MLA); the α3β4 antagonist 18-methoxycoronaridine (18-MC); and the non-nAChR drugs midazolam and cocaine.

RESULTS

In nicotine-trained mice, maximum nicotine-appropriate responding was 95% nicotine, 94% epibatidine, 63% varenicline, 58% cytisine, and less than 50% for RTI-102, PNU-282987, midazolam, and cocaine. In varenicline-trained mice, maximum varenicline-appropriate responding was 90% varenicline, 86% epibatidine, 74% cytisine, 80% RTI-102, 50% cocaine, and 50% or less for nicotine, PNU-282987, and midazolam. Drugs were studied to doses that abolished operant responding. Mecamylamine antagonized the discriminative stimulus effects, but not the rate-decreasing effects, of nicotine and varenicline. DHβE antagonized the discriminative stimulus and rate-decreasing effects of nicotine but not varenicline in either the nicotine or varenicline discrimination assays. The discriminative stimulus, but not the rate-decreasing, effects of epibatidine were antagonized by DHβE regardless of the training drug.

CONCLUSIONS

These results suggest that α4β2* nAChRs differentially mediate the discriminative stimulus effects of nicotine and varenicline, and suggest that varenicline has substantial non-α4β2 nAChR activity.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA.Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA. mcmahonl@uthscsa.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28028600

Citation

de Moura, Fernando B., and Lance R. McMahon. "The Contribution of Α4β2 and Non-α4β2 Nicotinic Acetylcholine Receptors to the Discriminative Stimulus Effects of Nicotine and Varenicline in Mice." Psychopharmacology, vol. 234, no. 5, 2017, pp. 781-792.
de Moura FB, McMahon LR. The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice. Psychopharmacology (Berl). 2017;234(5):781-792.
de Moura, F. B., & McMahon, L. R. (2017). The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice. Psychopharmacology, 234(5), 781-792. https://doi.org/10.1007/s00213-016-4514-4
de Moura FB, McMahon LR. The Contribution of Α4β2 and Non-α4β2 Nicotinic Acetylcholine Receptors to the Discriminative Stimulus Effects of Nicotine and Varenicline in Mice. Psychopharmacology (Berl). 2017;234(5):781-792. PubMed PMID: 28028600.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The contribution of α4β2 and non-α4β2 nicotinic acetylcholine receptors to the discriminative stimulus effects of nicotine and varenicline in mice. AU - de Moura,Fernando B, AU - McMahon,Lance R, Y1 - 2016/12/27/ PY - 2016/06/23/received PY - 2016/12/16/accepted PY - 2016/12/29/pubmed PY - 2017/12/1/medline PY - 2016/12/29/entrez KW - DHβE KW - Drug discrimination KW - Mecamylamine KW - Nicotine KW - Varenicline KW - β2 nAChRs SP - 781 EP - 792 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 234 IS - 5 N2 - RATIONALE: The extent to which non-α4β2 versus α4β2* nAChRs contribute to the behavioral effects of varenicline and other nAChR agonists is unclear. OBJECTIVES: The purpose of this study was to characterize the discriminative stimulus effects of varenicline and nicotine using various nAChR agonists and antagonists to elucidate possible non-α4β2 nAChR mechanisms. METHODS: Separate groups of male C57BL/6J mice were trained to discriminate varenicline (3.2 mg/kg) or nicotine (1 mg/kg). Test drugs included mecamylamine; the nAChR agonists epibatidine, nicotine, cytisine, varenicline, and RTI-102; the β2-containing nAChR antagonist dihydro-β-erythroidine (DHβE); the α7 nAChR agonist PNU-282987; the α7 antagonist methyllycaconitine (MLA); the α3β4 antagonist 18-methoxycoronaridine (18-MC); and the non-nAChR drugs midazolam and cocaine. RESULTS: In nicotine-trained mice, maximum nicotine-appropriate responding was 95% nicotine, 94% epibatidine, 63% varenicline, 58% cytisine, and less than 50% for RTI-102, PNU-282987, midazolam, and cocaine. In varenicline-trained mice, maximum varenicline-appropriate responding was 90% varenicline, 86% epibatidine, 74% cytisine, 80% RTI-102, 50% cocaine, and 50% or less for nicotine, PNU-282987, and midazolam. Drugs were studied to doses that abolished operant responding. Mecamylamine antagonized the discriminative stimulus effects, but not the rate-decreasing effects, of nicotine and varenicline. DHβE antagonized the discriminative stimulus and rate-decreasing effects of nicotine but not varenicline in either the nicotine or varenicline discrimination assays. The discriminative stimulus, but not the rate-decreasing, effects of epibatidine were antagonized by DHβE regardless of the training drug. CONCLUSIONS: These results suggest that α4β2* nAChRs differentially mediate the discriminative stimulus effects of nicotine and varenicline, and suggest that varenicline has substantial non-α4β2 nAChR activity. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/28028600/The_contribution_of_α4β2_and_non_α4β2_nicotinic_acetylcholine_receptors_to_the_discriminative_stimulus_effects_of_nicotine_and_varenicline_in_mice_ L2 - https://dx.doi.org/10.1007/s00213-016-4514-4 DB - PRIME DP - Unbound Medicine ER -