Removal of the olfactory bulbs from the rodent induces neuronal reorganisation and the expression of behavioural, neurochemical, neuroendocrine and immune changes that resemble those observed in major depressive disorder. As such this model is widely used to examine the neurobiological substrates that may underlie the pathophysiology of depression and screen antidepressant agents. One of the most consistent changes observed in the olfactory bulbectomised (OB) mouse model is hyperactivity on exposure to a novel stressful environment. This behavioural response is attenuated selectively by chronic, but not acute, antidepressant treatment. This chapter provides a detailed protocol on the establishment of the OB mouse model and assessment of OB-related increase in locomotor activity in the open field test. Experimental variables which may impact on the results will be presented in addition to a short troubleshooting guide.