Dopamine transporter mutant mice in experimental neuropharmacology

An opportunity to perform targeted genetic manipulations in mice has provided another dimension for modern pharmacological research. Genetically modified mice have become important tools to investigate functions of previously unexplored proteins, define mechanism of action of new and known pharmacological drugs, and validate novel targets for treatment of human disorders. One of the best examples of such use of genetic models in experimental pharmacology represents investigations involving mice deficient in the gene encoding the dopamine transporter (DAT). The dopamine transporter tightly regulates the extracellular dynamics of dopamine by recapturing released neurotransmitter into the presynaptic terminals, and genetic deletion of this protein results in profound alterations in both the presynaptic homeostasis and the extracellular dynamics of dopamine. By using this model of severe dopaminergic dysregulation, significant progress has been made in defining the major target of psychotropic drugs, understanding the mechanisms of their action, unraveling novel signaling events relevant for dopaminergic transmission, and mapping neuronal pathways involved in dopamine-related behaviors. Furthermore, DAT mutant mice provided an opportunity to model in vivo conditions of extreme dopaminergic dysfunction that could be relevant for human disorders such as ADHD, schizophrenia, and Parkinson's disease and, thus, could serve as test systems for developing novel treatments for these and related disorders.