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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 - PubMed

. 2018 May;235(5):1439-1453.

doi: 10.1007/s00213-018-4853-4. Epub 2018 Feb 18.

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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

Sarah E Maggio et al. Psychopharmacology (Berl). 2018 May.

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.

Keywords: (R)-modafinil; Alcohol; Co-use; Ethanol; Nicotine; R-bPiDI; Varenicline.

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Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1

Chemical structures of A) varenicline (6,7,8,9-tetrahydro-6,10-methano-6H pyrazino[2,3-h][3]benzazepine), B) r-bPiDI (1,10-bis(3-methyl-5,6-dihydropyridin-1(2H)-yl)decane), and C) RMOD, (R)-modafinil (2-[(R)-(diphenylmethyl)sulfinyl]acetamide)

Fig. 2
Fig. 2

Experiment 1 acquisition across sessions for A) EtOH consumption in Phase 1 (EtOH alone), B) EtOH consumption in Phase 3, C) water consumption in Phase 1 (EtOH alone), D) water consumption in Phase 3 (nicotine and EtOH), E) number of active and inactive lever presses for nicotine in Phase 2 and F) number of active vs. inactive lever presses for nicotine in Phase 3. Values represent mean±SEM

Fig. 3
Fig. 3

Experiment 1 total intake across the access phases. Graphs depict average intake differences for A) EtOH consumption in Phase 1 (EtOH alone) vs Phase 3 (EtOH and nicotine), B) water consumption in Phase 1 vs Phase 3, and C) number of infusions of nicotine in Phase 2 (nicotine alone) vs Phase 3. Values represent mean±SEM. *p < 0.05 vs Phase 1 or 2

Fig. 4
Fig. 4

Experiment 1 scatter plot of individual rats showing a significant negative correlation between EtOH consumption and number of nicotine infusions during Phase 3 (EtOH and nicotine); r = −0.58, p < 0.05

Fig. 5
Fig. 5

Experiment 1 blood EtOH concentration (BEC) in Phases 1 (EtOH alone) and 3 (EtOH and nicotine). Values represent mean±SEM BEC in mg/dL of tail blood. *p < 0.05 vs Phase 1

Fig. 6
Fig. 6

Experiment 1 pretreatment with varenicline (0 and 3 mg/kg) in Phase 3 (EtOH and nicotine) (n = 5). Graphs depict the effects of varenicline on A) EtOH consumption, B) water consumption, C) number of active lever presses for nicotine, and D) number of inactive lever presses. Values represent mean±SEM. *p < 0.05 vs vehicle (0)

Fig. 7
Fig. 7

Experiment 1 pretreatment with r-bPiDI (0, 10, and 20 mg/kg) in Phase 3 (EtOH and nicotine) (n = 17). Graphs depict the effects of r-bPiDI on A) EtOH consumption, B) water consumption, C) number of active lever presses for nicotine, and D) number of inactive lever presses. Values represent mean±SEM. *p < 0.05 vs vehicle (0)

Fig. 8
Fig. 8

Experiment 1 pretreatment with RMOD (0, 30, and 56 mg/kg) in Phase 3 (EtOH and nicotine) (n = 5). Graphs depict the effects of RMOD on A) EtOH consumption, B) water consumption, C) number of active lever presses for nicotine, and D) number of inactive lever presses. Values represent mean±SEM. *p < 0.05 vs vehicle (0)

Fig. 9
Fig. 9

Experiment 1 within-session nicotine self-administration as active lever presses per 10-min interval following pretreatments with A) varenicline (0 and 3 mg/kg), B) r-bPiDI (0, 10, and 20 mg/kg), and C) RMOD (0, 30, 56, and 100 mg/kg). Values represent mean±SEM. *p < 0.05 vs vehicle (0)

Fig. 10
Fig. 10

Experiment 2 pretreatment with varenicline (0 and 3 mg/kg), r-bPiDI (0, 10, and 20 mg/kg), and RMOD (0, 30, and 56 mg/kg) (n = 8). Graphs depict the effects of varenicline on A) EtOH consumption and B) water consumption, the effects of r-bPiDI on C) EtOH consumption and D) water consumption, and the effects of RMOD on E) EtOH consumption and F) water consumption. Values represent mean±SEM. *p < 0.05 vs vehicle (0)

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References

    1. (2017) Alcohol Facts and Statistics. In: Alcoholism NIoAAa (ed). U.S. Department of Health and Human Services
    1. Avelar AJ, Cao J, Newman AH, Beckstead MJ (2017) Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons. Neuropharmacology 123: 410–419. - PMC - PubMed
    1. Bardo MT, Green TA, Crooks PA, Dwoskin LP (1999) Nornicotine is self-administered intravenously by rats. Psychopharmacology 146: 290–6. - PubMed
    1. Barkley-Levenson AM, Crabbe JC (2014) High drinking in the dark mice: a genetic model of drinking to intoxication. Alcohol (Fayetteville, NY) 48: 217–23. - PMC - PubMed
    1. Beckmann JS, Meyer AC, Pivavarchyk M, Horton DB, Zheng G, Smith AM, Wooters TE, McIntosh JM, Crooks PA, Bardo MT, Dwoskin LP (2015) r-bPiDI, an alpha6beta2* Nicotinic Receptor Antagonist, Decreases Nicotine-Evoked Dopamine Release and Nicotine Reinforcement. Neurochemical research 40: 2121–30. - PMC - PubMed

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