Drug discrimination and neurochemical studies in α7 null mutant mice: tests for the role of nicotinic α7 receptors in dopamine release

• Published in: Psychopharmacology 2009, Vol.203 (2), p.399-410
• Main Authors: Quarta, Davide, Naylor, Christopher G., Barik, Jacques, Fernandes, Cathy, Wonnacott, Susan, Stolerman, Ian P.
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychiatry
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-008-1281-x

Rationale The nicotine discriminative stimulus has been linked to β2-containing (β2*) nicotinic receptors, with little evidence of a role for α7 nicotinic receptors, because nicotine discrimination was very weak in β2 null mutant mice but normal in α7 mutants. Objectives As both α7 and β2* nicotinic receptors have been implicated in nicotine-stimulated dopamine overflow, this study focused on the dopamine-mediated element in the nicotine stimulus by examining cross-generalisation between amphetamine and nicotine. Materials and methods Male α7 nicotinic receptor null mutant mice and wild-type controls were bred in-house and trained to discriminate nicotine (0.8 mg/kg) or (+)-amphetamine (0.6 mg/kg) from saline in a two-lever procedure with a tandem VI-30 FR-10 schedule of food reinforcement. Dopamine release from striatal slices was determined in parallel experiments. Results An α7 nicotinic receptor-mediated component of dopamine release was demonstrated in tissue from wild-type mice using choline as a selective agonist. This response was absent in tissue from null mutant animals. The mutation did not influence acquisition of drug discriminations but subtly affected the results of cross-generalisation tests. In mice trained to discriminate nicotine or amphetamine, there was partial cross-generalisation in wild-type mice and, at certain doses, these effects were attenuated in mutants. Further support for an α7 nicotinic receptor-mediated component was provided by the ability of the α7 nicotinic receptor antagonist methyllycaconitine to attenuate responses to nicotine and amphetamine in wild-type mice. Conclusions These findings support the concept of an α7 nicotinic receptor-mediated dopaminergic element in nicotine discrimination, warranting further tests with selective dopamine agonists.