Reciprocal interactions between central 5-HT system and hypothalamo-pituitary-adrenal (HPA) axis are of particular relevance with regard to depression, in which alterations of both systems have been evidenced. In order to further explore these interactions, two models of mutant mice have been used. They consisted of knock-out mice lacking the 5-HT transporter (5-HTT-/-) and of transgenic mice with impaired glucocorticoid receptor (GR-i) expression. Under control conditions. the functional properties of 5-HT(1A) autoreceptors in GR-i mice were as in their paired wild-type. However, both chronic stress and long term treatment with fluoxetine induced abnormal adaptive changes in 5-HT(1A) autoreceptor functioning in GR-i mice. On the other hand, a marked desensitization of 5-HT(1A) autoreceptors was found in 5-HTT-/- mice as compared with paired wild-type animals, and this phenomenon was further enhanced by exposure to stressful conditions. These data show that alterations 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.