Corticotropin-releasing hormone (CRH) overproduction and serotonergic dysfunction have both been implicated in a range of psychiatric disorders, such as anxiety and depression, and several studies have shown interactions between these two neurotransmitter systems. In this study, we investigated the effects of CRH challenge on hypothalamo-pituitary-adrenal (HPA) axis activity in female transgenic mice overproducing CRH. Furthermore, the effects of mild stress on HPA axis activity and body temperature were investigated in these mice. Pre- and post-synaptic 5-HT1A receptor function were studied by monitoring body temperature and plasma corticosterone levels after challenge with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propyl-amino)-tetralin (8-OH-DPAT). Hypothermia in response to 8-OH-DPAT treatment did not differ between transgenic and wild type mice, indicating unaltered somatodendritic 5-HT1A autoreceptor function in mice overproducing CRH. In wild type mice 8-OH-DPAT increased plasma corticosterone levels, but not in transgenic animals. CRH injection, however, increased corticosterone levels in both groups. These data suggest desensitization of post-synaptic, but not pre-synaptic, 5-HT1A receptors in mice overproducing CRH. These findings resemble those seen in depressed patients following 5-HT1A challenge, which is in accord with the hypothesized role of CRH in the pathogenesis of depression.