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The Nicotinic α6-Subunit Selective Antagonist bPiDI Reduces Alcohol Self-Administration in Alcohol-Preferring Rats

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Abstract

Cigarettes and alcohol are the most abused substances in the world and are commonly co-abused. Nicotine primarily acts in the brain on nicotinic acetylcholine receptors (nAChR), which are also a target for alcohol. The alpha6 subunit of nAChR is expressed almost exclusively in the brain reward system and may modulate the rewarding properties of alcohol and nicotine. Recently, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI) was synthesized as a selective, brain penetrant α6 subunit antagonist that reduces nicotine self-administration. The current study aimed to examine the effects of bPiDI on alcohol self-administration in inbred alcohol-preferring (iP) rats. Adult, male iP rats were trained to self-administer alcohol or sucrose. Once stable responding was achieved, rats were injected with bPiDI (1, 3 mg/kg, i.p.) and tested for self-administration under fixed and progressive ratio schedules of reinforcement. They subsequently underwent extinction, in which no rewards or cues were presented in the operant chambers. Then, they were injected with bPiDI prior to testing for cue-induced reinstatement of reward seeking. bPiDI (3 mg/kg) significantly reduced alcohol self-administration in both fixed and progressive ratios without any effects on sucrose self-administration or locomotor activity. In contrast, bPiDI (3 mg/kg) did not inhibit cue-induced reinstatement of either alcohol or sucrose seeking. The results support the involvement of α6 containing nAChR in reinforcing effects of alcohol, but not relapse to alcohol-seeking, without any impact on responding for a natural reward or general activity. bPiDI may be a potential lead molecule for a therapeutic strategy to limit nicotine and alcohol consumption.

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Acknowledgments

This study was supported by the NHMRC Australia (Project Grant 628680), Royal Golden Jubilee PhD Program (PHD/0253/2552), Thailand Research Fund (DPG5780001), Mahidol University and a Committee for Aid and Education in Neurochemistry Grant (CAEN) from the International Society for Neurochemistry (ISN). AJL is a Fellow of the NHMRC (1020737). We also acknowledge the Victorian Government’s Operational Infrastructure Support Program.

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Authors and Affiliations

  1. Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand

    Jirawoot Srisontiyakul & Piyarat Govitrapong

  2. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Royal Parade, Parkville, VIC, 3052, Australia

    Hanna E. Kastman, Elena V. Krstew & Andrew J. Lawrence

  3. Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand

    Piyarat Govitrapong

  4. Florey Department of Neuroscience, University of Melbourne, Parkville, VIC, Australia

    Andrew J. Lawrence

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  1. Jirawoot Srisontiyakul
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Correspondence to Andrew J. Lawrence.

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Srisontiyakul, J., Kastman, H.E., Krstew, E.V. et al. The Nicotinic α6-Subunit Selective Antagonist bPiDI Reduces Alcohol Self-Administration in Alcohol-Preferring Rats. Neurochem Res 41, 3206–3214 (2016). https://doi.org/10.1007/s11064-016-2045-3

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  • DOI: https://doi.org/10.1007/s11064-016-2045-3

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