Contribution of Serotonergic Transmission to the Motor and Cognitive Effects of High-Frequency Stimulation of the Subthalamic Nucleus or Levodopa in Parkinson’s Disease

Abstract

Although they are effective at treating the motor impairments that are the core symptoms of Parkinson's disease, current treatments, namely L: -3,4-dihydroxyphenylalanine (L: -DOPA), the gold standard medication and high-frequency stimulation of the subthalamic nucleus (HFS-STN), can lead to cognitive and mood alterations. Many of these side effects, such as depression, anxiety and sleep disturbances, could be related to abnormal functioning of the serotonergic system, but much basic research remains to be done. Molecular studies in humans and animal models of the disease have reported diverse drastic changes to the serotonergic system. It has also been shown that the serotonergic system both plays a major role in the mechanism of action of the current therapies and is altered by the therapies. It has been reported that HFS-STN decreases serotonin release in several regions, mostly via inhibition of serotonergic neuron activity. The involvement of serotonergic neurons in L: -DOPA treatment is even more significant. First, serotonergic neurons, able to convert exogenous L: -DOPA to dopamine, are a major site to release dopamine throughout the brain. Second, the substitution of serotonin by newly synthesized dopamine in serotonin neurons leads to acute and chronic alteration of serotonin release and metabolism. Therefore, both therapeutic approaches, via distinct mechanisms, decrease serotonergic system activity and, rather than alleviating cognitive or mood disorders, tend to aggravate them. Molecular strategies targeting the serotonergic system are being developed and could be decisive in limiting L: -DOPA-induced dyskinesia, as well as mood and cognitive symptoms produced by antiparkinsonian therapies.

Personality, dopamine, and Parkinson's disease: Insights from subthalamic stimulation

“…In the present study, however, we cannot rule out an impact of STN‐DBS on the serotonergic system that could participate to the increase in harm avoidance. Indeed, several fundamental studies have shown results consistent with a decrease in serotonergic tonus induced by STN‐DBS . However this serotonergic modulation seems insufficient by itself to explain the increased prevalence of harm avoidance.…”

Serotonin Impairment in CSF of PD Patients, without an Apparent Clinical Counterpart

“…It is possible that in a larger sample of patients, undergoing a prolonged follow-up study, low levels of 5-HT would correlate with specific sub-items related to unconventional aspect of non-motor symptoms well beyond those testable through depression or apathy rating scales, including BDI, HSD or AES. Coping strategies, for instance, are largely impaired in PD patients whereas reduced compliance and lack of adhesion to therapy is largely recognized despite consistent L-dopa-therapy and STN-DBS treatment [22].…”

Serotonin2C Receptors and the Motor Control of Oral Activity

“…Indeed, high frequency stimulation (HFS) or lesions of STN has been shown to significantly alleviate oral dyskinesias in rats [79, 94]. STN-HFS in sham-lesioned and DA-lesioned rats has been shown to reduce 5-HT release in several regions, in part via the inhibition of 5-HT neuron activity [95]. Similarly, an action in the output regions of the basal ganglia may be envisioned.…”