Hyperactivity of the stress axis is thought to be one of the fundamental underlying drivers of psychiatric conditions such as generalised anxiety and depression. This has led us and others to develop pharmacological approaches to modify neural stress pathways in the brain. Along these lines, we have recently discovered that the neuropeptide RFRP-3 induces anxious behaviour and enhances acute stress responses in mice. Remarkably, blockade of its receptor with a novel antagonist called GJ14 overcomes these responses. Using powerful new transgenic mouse lines and single cellular through to in vivo behavioural measurements, we will evaluate the role of RFRP-3 on activity of the cells controlling the stress axis, stress hormone secretion and various anxiety-related behaviours. We will then develop and evaluate new RFRP-3 receptor antagonists with improved ability to enter the brain following oral delivery, potentially opening an entirely new avenue for treating stress and anxiety related disorders.