Fall 2002

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Drug discrimination studies in knockout mice shed light on the molecular basis of nicotine dependence

This first full report of drug discrimination research in genetically modified mice illustrates the power of this approach for linking drug effects in the living organism to their actions at the molecular level. Thus, studies in knockout mice lacking all beta-2 containing nicotinic receptors have helped to define the role of such receptors in nicotine dependence. The twelve known subunits of neuronal nicotinic receptors form complex structures associated with many physiological and pharmacological functions. The most common subtype of nicotinic receptor in the brain contains the alpha-4 and beta-2 subunits, but the precise receptor subtypes at which the dependence process originates are not known. Wild-type (control) and knockout mice were trained in a two-lever nicotine discrimination procedure with food reinforcers. Baseline rates of lever-pressing of control and knockout mice did not differ. Control mice acquired discrimination of nicotine rapidly and exhibited steep nicotine dose-response curves. In striking contrast, mutant mice failed to acquire nicotine discrimination and exhibited flat dose-response curves that did not deviate from the control level, indicating the abolition of stimulus control by the training doses of nicotine. Both control and knockout mice acquired discrimination of a very large dose of nicotine although discrimination performance was weak in the knockouts. Nicotine initially reduced response rates in all mice, and tolerance developed to this effect in both control and knockout animals. Both genotypes acquired the discrimination of morphine with similar degrees of accuracy, and dose-response curves for morphine discrimination were indistinguishable. The ability of nicotine to produce conditioned taste aversions was also weakened in the knockout mice. It is concluded that nicotinic receptors containing the beta-2 subunit play a major role in the stimulus properties of nicotine that are thought to reflect psychological aspects of tobacco dependence. However, beta-2 containing receptors appear to have a less crucial role in nicotine tolerance. Recognition that different receptor mechanism may underlie different aspects of nicotine dependence may aid the development of pharmacotherapies for smoking cessation.

Based on: Shoaib M, Gommans J, Morley A, Stolerman IP, Grailhe R, Changeux J-P (2002) The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion. Neuropharmacology 42: 530-539.

Prepared by: Ian Stolerman
Institute of Psychiatry, King's College London

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