Intervening with serotonergic neurotransmission can have profound effects on mobility. For instance, the peripheral administration of the 5HT(2A/c) agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), changes the locomotor activity substantially. Locomotor activity is classically linked to the basal ganglia, in which the subthalamic nucleus (STN) plays a pivotal role. In this study, we tested the hypothesis that deep brain stimulation (DBS) of the STN modulates DOI-induced hypomobility. Rats were implanted with stimulating electrodes at the level of the STN and were tested in an open field (OF) task in various conditions (stimulation on/off, in combination with DOI treatment). We found that DOI administration (i.p.) reduced the behavioural activity of the animals and that STN HFS reversed these effects. This study provides the first evidence that the therapeutic effect of STN HFS may also be mediated by a 5-HT-dependent mechanism.