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Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior

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Abstract

Rationale and objectives

The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, α-conotoxin MII (αCtxMII, α3β2*, β3*, α6*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-β-erythroidine (DHβE, α4β2*), and methyllycaconitine (MLA, α7*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats.

Methods

The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. αCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHβE, and MLA were administered systemically.

Results

αCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHβE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation.

Conclusions

Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR α3β2*, β3, and/or α6* receptor subunits might be of therapeutic value for the treatment of alcoholism.

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Acknowledgements

This work was supported by grants from the Alcohol Research Council of the Swedish Retailing Monopoly, the Karolinska Institutet, the Swedish Labor Market Insurance (AFA), the Swedish Science Research Council (projects 4247, 7688, 15052), Wilhelm and Martina Lundgrens Scientific Foundation, Rådman and Fru Ernst Collianders Foundation, Stiftelsen Olle Engkvist Byggmästare, Knut and Alice Wallenberg Foundation, The Adlerbertska Foundation, the Filip Lundbergs Foundation, the Längmanska Cultural Foundation, and the Royal Society of Arts and Sciences in Göteborg.

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  1. Department of Clinical Neuroscience, Division of Drug Dependence, Karolinska University Hospital, Bldg M1:01, 17176, Stockholm, Sweden

    Alexander Kuzmin & Sture Liljequist

  2. Institute of Neuroscience and Physiology, Section of Pharmacology, Göteborg University, Göteborg, Sweden

    Elisabet Jerlhag & Jörgen Engel

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  1. Alexander Kuzmin
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  2. Elisabet Jerlhag
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Correspondence to Sture Liljequist.

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Kuzmin, A., Jerlhag, E., Liljequist, S. et al. Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior. Psychopharmacology 203, 99–108 (2009). https://doi.org/10.1007/s00213-008-1375-5

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