GABA transporter1 (GAT1) inhibition mediates distinct emotional and cognitive processes and represents a possible treatment strategy compensating genetic polymorphisms in panic disorder

There is increasing evidence for a dysregulation of the GABAergic system in the pathophysiology of anxiety disorders. We, therefore, first assessed the characteristics of tiagabine, a selective GABA reuptake inhibitor, in an animal model of anxiety-related and depression-like behavior. C57BL/6J mice received acute and chronic administration of tiagabine. Anxiety-related behavior was tested using the elevated plus maze and the modified hole board. Screening for antidepressant-like effects we performed a orced swimming test. Alterations in cognitive performance were assessed by measuring aquisition of a simple operant task in the modified hole board. So far, tiagabine treatment significantly decreased anxiety-related and depression-like behavior with no adverse effects on cognition and motor function.We further studied whether the susceptibility to develop panic disorder is related to polymorphisms in the GAT1-gene in patients suffering from panic disorder. We performed an gene association study with 15 single nucleotide polymorphisms (SNPs) as genetic markers in subjects ascertained from the MPI anxiety disorders outpatient clinic. Our results revealed an association between a SNP in intron 2 of the GAT1-gene and panic disorder (p<0.0001). The results of our „translational study“ strongly support the assumption that the inhibition of the GABA reuptake by tiagabine may be a novel pharmacological strategy in the treatment of anxiety and mood disorders.