Neurogenetics of emotional reactivity to stress in animals

There is much evidence for the involvement of central monoaminergic systems, the key targets of stress, in the regulation of mood. Animal and human findings indicate that genetics play a role in the etiology of mood disorders, and so we selected divergent inbred rat strains according to their anxiety-related behaviors on exposure to novel environments. We compared these strains for psychoneuroendocrine response to stressors and/or antidepressants. Molecular genetic studies were also performed to localize the genomic regions associated with these strain-dependent anxiety profiles. We then examined human results indicating that allelic variations in the serotonin transporter (5-HTT) may play a role in the etiology of neuroticism and depression. Thus, we compared inbred rat strains for the 5-HTT, with regard to central and peripheral (platelet) protein expression and function, and the consequences of local application of a selective serotonin reuptake inhibitor (SSRI) on extracellular serotonin (5-HT) levels. Our results indicate that spontaneously hypertensive rats and Lewis rats (LEW) selectively diverge in terms of anxiety-related behaviors and that this divergence is located on chromosome 4. The use of social defeat in LEW and the analysis of its psychoneuroendocrine consequences strongly suggest that such a paradigm, which is sensitive to repeated SSRI treatment, models posttraumatic stress disorder. The Wistar-Kyoto rat may be an adequate model to study the consequences of a genetically driven hypersensitivity to stress and noradrenergic antidepressants. Our most recent findings show that the Fischer 344 and LEW strains differ in protein expression and function of hippocampal and platelet 5-HTT; the divergence in protein expression is not due to allelic variations in the gene-coding sequences and leads to marked differences in extracellular 5-HT levels under basal conditions or SSRI. These examples illustrate how the use of inbred rat strains may complement our knowledge on the genetics of behavior, in the same way as the use of transgenic mice.