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Effects of the nicotinic agonist varenicline, nicotinic antagonist r-bPiDI, and DAT inhibitor (R)-modafinil on co-use of ethanol and nicotine in female P rats

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Abstract

Rationale

Co-users of alcohol and nicotine are the largest group of polysubstance users worldwide. Commonalities in mechanisms of action for ethanol (EtOH) and nicotine proposes the possibility of developing a single pharmacotherapeutic to treat co-use.

Objectives

Toward developing a preclinical model of co-use, female alcohol-preferring (P) rats were trained for voluntary EtOH drinking and i.v. nicotine self-administration in three phases: (1) EtOH alone (0 vs. 15%, two-bottle choice), (2) nicotine alone (0.03 mg/kg/infusion, active vs. inactive lever), and (3) concurrent access to both EtOH and nicotine. Using this model, we examined the effects of (1) varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist with high affinity for the α4β2* subtype; (2) r-bPiDI, a subtype-selective antagonist at α6β2* nAChRs; and (3) (R)-modafinil, an atypical inhibitor of the dopamine transporter (DAT).

Results

In phases 1 and 2, pharmacologically relevant intake of EtOH and nicotine was achieved. In the concurrent access phase (phase 3), EtOH consumption decreased while nicotine intake increased relative to phases 1 and 2. For drug pretreatments, in the EtOH access phase (phase 1), (R)-modafinil (100 mg/kg) decreased EtOH consumption, with no effect on water consumption. In the concurrent access phase, varenicline (3 mg/kg), r-bPiDI (20 mg/kg), and (R)-modafinil (100 mg/kg) decreased nicotine self-administration but did not alter EtOH consumption, water consumption, or inactive lever pressing.

Conclusions

These results indicate that therapeutics which may be useful for smoking cessation via selective inhibition of α4β2* or α6β2* nAChRs, or DAT inhibition, may not be sufficient to treat EtOH and nicotine co-use.

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Acknowledgements

Supported by NIH grants R01AA025591, UL1TR000117, U19DA17548, P50DA05312, T32DA016176, and U24AA015512.

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Authors and Affiliations

  1. Department of Psychology, University of Kentucky, Lexington, KY, 40536, USA

    Sarah E. Maggio, Meredith A. Saunders, Thomas A. Baxter, Mark A. Prendergast & Michael T. Bardo

  2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 40536, USA

    Kimberly Nixon & Linda P. Dwoskin

  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas, Little Rock, AR, 72205, USA

    Guangrong Zheng & Peter Crooks

  4. Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse-Intramural Research Program, National Institutes of Health, Baltimore, MD, 21224, USA

    Rachel D. Slack & Amy H. Newman

  5. Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Richard L. Bell

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  1. Sarah E. Maggio
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Correspondence to Michael T. Bardo.

Ethics declarations

All testing procedures occurred during the light phase (7:00 am–7:00 pm) were in accordance with the NIH Guide for the Care and Use of Laboratory Animals (8th edition, 2011) and were approved by the Institutional Animal Care and Use Committee at the University of Kentucky.

Conflict of interest

The University of Kentucky holds a patent on r-bPiDI and a potential royalty stream to Dwoskin and Crooks may occur consistent with University of Kentucky policy.

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Maggio, S.E., Saunders, M.A., Baxter, T.A. et al. Effects of the nicotinic agonist varenicline, nicotinic antagonist r-bPiDI, and DAT inhibitor (R)-modafinil on co-use of ethanol and nicotine in female P rats. Psychopharmacology 235, 1439–1453 (2018). https://doi.org/10.1007/s00213-018-4853-4

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