Psychiatric Aspects of Parkinson’s Disease in Animal Models of Deep Brain Stimulation of the Subthalamic Nucleus

Abstract

It is well established that deep brain stimulation (DBS) of the subthalamic nucleus (STN) has beneficial effects on motor symptoms of Parkinson’s disease (PD). Unfortunately, these can be overshadowed by psychiatric side effects, including depression and suicide. The underlying mechanism is unknown, but it is generally believed that low mood is related to a dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system. Recent animal experiments have demonstrated that bilateral STN DBS with clinically relevant parameters (130 Hz, 60 μs, 100–200 μA) inhibits 5-HT neurotransmission in the brain. In anaesthetized rats bilateral STN DBS caused a significant inhibition of 5-HT neuronal activity in the dorsal raphe nucleus (DRN). Moreover, both unilateral and bilateral STN DBS inhibited 5-HT release in the forebrain of anaesthetized and freely moving rats. A direct STN projection to the DRN does not exist, making a multisynaptic pathway most likely. On the basis of increased expression of c-Fos, a marker of neuronal activity, it was found that the medial prefrontal cortex and lateral habenula potentially mediate the inhibitory effect of STN DBS on the DRN 5-HT system. Previously these two brain regions have been extensively described in inhibitory control of DRN 5-HT neurons. Behavioural evaluation showed that bilateral STN DBS also induced depressive-like behaviour in the forced swim test and increased interaction in the social interaction test. Interestingly, depressive-like behaviour could be prevented by treatment with a 5-HT reuptake inhibitor. Thus, STN DBS induced inhibition of 5-HT transmission via a multisynaptic anatomical pathway may underlie the development of psychiatric complications such as depression. STN DBS treated patients with these symptoms may benefit from drug treatment focusing on 5-HT transmission.