Journal
PSYCHOPHARMACOLOGY
Volume 203, Issue 1, Pages 99-108Publisher
SPRINGER
DOI: 10.1007/s00213-008-1375-5
Keywords
Ethanol self-administration; Ethanol relapse; Nicotinic AChR subunits; alpha-conotoxin MII (alpha CtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*); Mecamylamine Dihydro-beta-erythroidine (DH beta E, alpha(4)beta(2)*); Methyllycaconitine (MLA, alpha 7*)
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Funding
- Alcohol Research Council of the Swedish Retailing Monopoly
- Karolinska Institutet
- Swedish Labor Market Insurance (AFA)
- Swedish Science Research Council [4247, 7688, 15052]
- Wilhelm and Martina Lundgrens Scientific Foundation
- Radman and Fru Ernst Collianders Foundation
- Stiftelsen Olle Engkvist Byggm stare
- Knut and Alice Wallenberg Foundation
- The Adlerbertska Foundation
- Filip Lundbergs Foundation
- Langmanska Cultural Foundation
- Royal Society of Arts and Sciences in Goteborg
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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, alpha-conotoxin MII (alpha CtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-beta-erythroidine (DH beta E, alpha(4)beta(2)*), and methyllycaconitine (MLA, alpha(7)*) 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. 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. alpha CtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DH beta E, and MLA were administered systemically. alpha CtxMII 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. DH beta E 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. 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 alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism.
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