Drug discrimination and neurochemical studies in alpha 7 null mutant mice: tests for the role of nicotinic alpha 7 receptors in dopamine release

The nicotine discriminative stimulus has been linked to beta 2-containing (beta 2*) nicotinic receptors, with little evidence of a role for alpha 7 nicotinic receptors, because nicotine discrimination was very weak in beta 2 null mutant mice but normal in alpha 7 mutants. As both alpha 7 and beta 2* 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. Male alpha 7 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. An alpha 7 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 alpha 7 nicotinic receptor-mediated component was provided by the ability of the alpha 7 nicotinic receptor antagonist methyllycaconitine to attenuate responses to nicotine and amphetamine in wild-type mice. These findings support the concept of an alpha 7 nicotinic receptor-mediated dopaminergic element in nicotine discrimination, warranting further tests with selective dopamine agonists.