5-HT3A Receptor Subunit is Required for 5-HT3 Antagonist-Induced Reductions in Alcohol Drinking

University of Dundee, Dundee, Scotland, United Kingdom
Neuropsychopharmacology (Impact Factor: 7.05). 11/2004; 29(10):1807-13. DOI: 10.1038/sj.npp.1300498
Source: PubMed


The ionotropic serotonin subtype-3 (5-HT3) receptor has emerged as a potential therapeutic target in the treatment of alcohol abuse and alcoholism because selective pharmacological antagonists reduce alcohol consumption in preclinical and clinical models. 5-HT binds to the extracellular N-terminus of the 5-HT(3A) receptor subunit but receptor activation is also enhanced by distinct allosteric sites, which indicates the presence of other receptor subunits. It is not known if specific molecular subunits of the 5-HT3 receptor modulate alcohol drinking. To address this issue, we characterized acute locomotor response to alcohol and alcohol consumption in a two-bottle home-cage procedure by congenic C57BL/6J mice with a targeted deletion of the 5-HT(3A) receptor subunit gene. 5-HT(3A)-null mice did not differ from wild-type littermate controls on measures of spontaneous locomotor activity, habituation to a novel environment, or locomotor response to ethanol (0, 0.5, 1, or 2 g/kg). Moreover, null mice did not differ from controls on measures of ethanol (2-10%) intake and preference during or after a two-bottle home-cage sucrose fading procedure. Systemic administration of the 5-HT3 antagonist LY-278,584 (0-10 mg/kg) decreased intake of both sweetened (2% sucrose+10% ethanol) and unsweetened (10% ethanol) ethanol in wild-type mice only. These findings indicate that reduction of alcohol drinking produced by 5-HT3 antagonism is dependent on the presence of 5-HT(3A)-containing receptors.

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Available from: Stephen P Kelley, Sep 11, 2014
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    • "All mice were single-housed for this study, and daily fluid intake was recorded. At the start of the 6 weeks of ethanol consumption, the modified sucrose-fading technique (Samson , 1986) was adapted to incentivize the mice to the ethanol solution similar to previous studies (Becker & Lopez, 2004; Camarini & Hodge, 2004; Hodge et al., 2004; Sanna et al., 2011). At all times, an alternative source of untreated water was freely available to all mice. "
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    • "The differences in experimental findings may be explained by strain or line of rat or the antagonist itself, some of which are not that selective for the 5-HT 3 receptor (Engleman et al., 2008). In a 5-HT 3A receptor knock-out study, the presence of the 5-HT 3A receptor was required for the selective 5-HT 3A receptor antagonist, LY-278-584, to reduce alcohol consumption, underscoring the importance of this receptor in alcohol consumption (Hodge et al., 2004). Transgenic mice overexpressing the 5-HT 3A receptor drank less alcohol than wild-type mice (Engel et al., 1998), but these mice had increased sensitivity to the low dose effects of alcohol (Engel and Allan, 1999). "
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    • "In the rodent, systemic treatment with 5-HT3 antagonists including ondansetron, tropisetron and LY-278,584 reduces stress-induced reinstatement of alcohol self-administration and reward-related place learning (Le et al., 2006; Matsuzawa et al., 1999). 5-HT3A-R knockout mice fail to show the normal reduction in voluntary ethanol consumption produced by 5-HT3-R antagonist LY-278,584, but otherwise show normal baseline consumption and sensitivity to the acute behavioral effects of ethanol (Hodge et al., 2004). A different phenotype is produced by postdevelopmental transgenic overexpression of 5-HT3-R in forebrain regions including the mPFC and amygdala (Engel et al., 1998; Harrell and Allan, 2003). "
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