Transgenic mice in drug dependence research.

Transgenic mice with null mutation of specific genes of the central nervous system obtained by homologous recombination, called also knock-out mice, have been recently used by behavioural neuroscientists to understand better the relevance of certain biological mechanisms of drug dependence or addiction. This article reviews some of the main contributions to this fastly developing field. As addictive drugs exert similar reinforcing effects both in humans and other mammals, changes in behavioural performance produced by the motivational effects of the addictive drugs in knock-out mice can give important information about the relevance of that particular gene product (eg a neurotransmitter receptor) for the pathogenicity of substance abuse disorders. In same cases the deletion of a given gene for a neurotransmitter receptor involved in the action of addictive drugs is associated with a phenotype that reproduces the effects obtained by the pharmacological administration of an antagonist for the same receptor. In other instances, surprising results are obtained, the most striking being the evidence that mice lacking the dopamine transporter gene, the most important binding site of cocaine, retain the capability to self-administer cocaine intravenously. Because the gene deletion is operative during embryogenesis, some adaptive compensatory mechanisms may produce unexpected results, suggesting caution in the interpretation of these results. The advent of tissue-specific inducible knock-out mice will soon produce a second revolution in the field of substance abuse research.