Interaction between the 5-HT system and the basal ganglia: functional implication and therapeutic perspective in Parkinson's disease

Abstract

The neurotransmitter serotonin (5-HT) has a multifaceted function in the modulation of information processing through the activation of multiple receptor families, including G-protein-coupled receptor subtypes (5-HT1, 5-HT2, 5-HT4-7) and ligand-gated ion channels (5-HT3). The largest population of serotonergic neurons is located in the midbrain, specifically in the raphe nuclei. Although the medial and dorsal raphe nucleus (DRN) share common projecting areas, in the basal ganglia (BG) nuclei serotonergic innervations come mainly from the DRN. The BG are a highly organized network of subcortical nuclei composed of the striatum (caudate and putamen), subthalamic nucleus (STN), internal and external globus pallidus (or entopeduncular nucleus in rodents, GPi/EP and GPe) and substantia nigra (pars compacta, SNc, and pars reticulata, SNr). The BG are part of the cortico-BG-thalamic circuits, which play a role in many functions like motor control, emotion, and cognition and are critically involved in diseases such as Parkinson's disease (PD). This review provides an overview of serotonergic modulation of the BG at the functional level and a discussion of how this interaction may be relevant to treating PD and the motor complications induced by chronic treatment with L-DOPA.

Keywords: 5-HT; L-DOPA induced dyskinesia; Parkinson's disease; basal ganglia; electrophysiology.

Figure 1

Simplified diagram of the basal ganglia circuits and altered serotonergic receptor expression in pathological states. Changes found in serotonergic receptor density in parkinsonian (left boxes) and dyskinetic (right boxes) patients or animals models compared to control conditions. Each nucleus and its modifications in receptor expression are encoded with the same color. GABAergic inhibitory pathways are represented in dark blue and glutamatergic excitatory pathways in red. Modulatory dopaminergic connections are indicated in green and serotonergic pathways in brown. DRN, dorsal raphe nucleus; GPi (EP), internal segment of the globus pallidus (entopeduncular nucleus); GPe, external segment of the globus pallidus; STN, subthalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata. r, rodent; m, monkey; h, human.