5-HT-HPA interactions in two models of transgenic mice relevant to major depression

Reciprocal interactions between central 5-HT system and hypothalamo-pituita ry-adrenal (HPA) axis are of particular relevance with regard to depression , in which alterations of both systems have been evidenced. In order to fur ther explore these interactions, two models of mutant mice have been used. They consisted of knock-out mice lacking the 5-HT transporter (5-HTT-/-) an d of transgenic mice with impaired glucocorticoid receptor (GR-i) expressio n. Under control conditions, the functional properties of 5-HT1A autorecept ors in GR-i mice were as in their paired wild-type. However, both chronic s tress and long term treatment with fluoxetine induced abnormal adaptive cha nges in 5-HT1A autoreceptor functioning in GR-i mice. On the other hand, a marked desensitization of 5-HT1A autoreceptors was found in 5-HTT-/- mice a s compared with paired wild-type animals, and this phenomenon was further e nhanced by exposure to stressful conditions. These data show that alteratio ns of HPA axis at the gene level has consequences on 5-HT neurotransmission , and reciprocally, that 5-HTT knock-out affects HPA-dependent responses to stress.