1. Drug discrimination and neurochemical studies in alpha7 null mutant mice: tests for the role of nicotinic alpha7 receptors in dopamine release.
- Author
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Quarta D, Naylor CG, Barik J, Fernandes C, Wonnacott S, and Stolerman IP
- Subjects
- Animals, Behavior, Animal drug effects, Binding, Competitive, Cell Membrane drug effects, Cell Membrane metabolism, Conditioning, Operant drug effects, Corpus Striatum metabolism, Discrimination, Psychological physiology, Male, Mice, Mice, Knockout, Radioligand Assay, Receptors, Nicotinic genetics, Reinforcement, Psychology, alpha7 Nicotinic Acetylcholine Receptor, Amphetamine pharmacology, Corpus Striatum drug effects, Discrimination, Psychological drug effects, Dopamine metabolism, Nicotine pharmacology, Receptors, Nicotinic physiology
- Abstract
Rationale: The nicotine discriminative stimulus has been linked to beta2-containing (beta2*) nicotinic receptors, with little evidence of a role for alpha7 nicotinic receptors, because nicotine discrimination was very weak in beta2 null mutant mice but normal in alpha7 mutants., Objectives: As both alpha7 and beta2* 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 alpha7 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 alpha7 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 alpha7 nicotinic receptor-mediated component was provided by the ability of the alpha7 nicotinic receptor antagonist methyllycaconitine to attenuate responses to nicotine and amphetamine in wild-type mice., Conclusions: These findings support the concept of an alpha7 nicotinic receptor-mediated dopaminergic element in nicotine discrimination, warranting further tests with selective dopamine agonists.
- Published
- 2009
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