Contribution of serotonergic transmission to the motor and cognitive effects of high-frequency stimulation of the subthalamic nucleus or levodopa in Parkinson’s disease

Sylvia Navailles, Philippe De Deurwaerdère
Mol Neurobiol. 2012-01-06; 45(1): 173-185
DOI: 10.1007/s12035-011-8230-0

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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.


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