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

D Quarta, C G Naylor, J Barik, C Fernandes, Susan Wonnacott, I P Stolerman

Research output: Contribution to journalArticle

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Abstract

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.
LanguageEnglish
Pages399-410
Number of pages12
JournalPsychopharmacology
Volume203
Issue number2
DOIs
StatusPublished - Apr 2009

Fingerprint

Dopamine Receptors
Nicotine
Nicotinic Receptors
Pharmaceutical Preparations
Amphetamine
Dopamine
Nicotinic Antagonists
Discrimination (Psychology)
Corpus Striatum
Reinforcement Schedule
Aptitude
Dopamine Agonists
Choline
Food
Mutation

Keywords

  • Acetylcholine receptor
  • Nicotinic receptors
  • Methyllycaconitine
  • Drug discrimination
  • Behaviour
  • Mice
  • Release
  • Dopamine
  • Monoamine
  • Nicotine
  • Amphetamine
  • Binding
  • Dopamine release

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Drug discrimination and neurochemical studies in alpha 7 null mutant mice: tests for the role of nicotinic alpha 7 receptors in dopamine release. / Quarta, D; Naylor, C G; Barik, J; Fernandes, C; Wonnacott, Susan; Stolerman, I P.

In: Psychopharmacology, Vol. 203, No. 2, 04.2009, p. 399-410.

Research output: Contribution to journalArticle

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abstract = "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.",
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