A molecular genetic approach to addiction by targeting components of the dopaminergic system | © dkfz.de

Dopaminergic projections from the ventral midbrain into the striatum act as a reward system of the brain and are responsible for the reinforcing effects of natural rewards like food or drugs of abuse, since there is a strong correlation between reinforcing properties of drugs and release of dopamine. Our goal is to identify the signaling pathways and changes in gene expression profiles that are induced by drugs of abuse which potentially may lead to addiction. In previous work we have demonstrated the importance of CREB for the development of drug dependence. To define the role of the GluR1, GluR2 and NR1 receptors in dopaminergic neurons, we have generated mutations in these genes using BAC-based transgenes expressing Cre recombinase under the control of the regulatory elements of the dopamine transporter gene. We have also successfully developed an inducible line expressing a Cre fusion protein with a mutated ligand binding domain of the estradiol receptor. Abolition of GluR1 and NR1 function results in lack of synaptic strengthening in dopaminergic neurons, but locomotor sensitization and conditioned place preference is not altered. However, extinction of drug-seeking behaviour was absent in mice lacking GluR1 and reinstatement was abolished in NR1 mutants, suggesting that these receptors control the persistence of cocaine seeking.