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.

NLX-112, a novel 5-HT 1A receptor agonist for the treatment of l -DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat

“…Correspondingly, L-DOPAinduced Abnormal Involuntary Movements (AIMs; a preclinical analogue of LID) in rat are abolished following the lesion of serotoninergic neurons with 5,7-di-hydroxytryptamine (5, (Carta et al, 2007). In addition, activation of inhibitory 5-HT 1A somatodendritic autoreceptors expressed on serotonergic raphe neurons reduces their activity and decreases dyskinesia (Eskow et al, 2009); recently reviewed in (Cenci, 2014;Miguelez et al, 2014;Politis et al, 2014).…”

Activity of serotonin 5-HT1A receptor ‘biased agonists’ in rat models of Parkinson's disease and l-DOPA-induced dyskinesia

“…Pharmacological interventions aiming to dampen DA release from serotonin neurons could therefore be effective in attenuating LID. One way to achieve this goal is through the activation of somatodendritic serotonin (5-HT) 5-HT 1A receptors which are expressed on 5-HT neurons in the Raphe nuclei and inhibit their activity (recently reviewed in (Miguelez et al, 2014;Politis et al, 2014). However, 5-HT 1A receptors are also expressed in other brain regions that influence motor function.…”

What Gene Mutations Affect Serotonin in Mice?

“…These genes included those associated with the well-known neurodegenerative disease Parkinson’s (Lrrk2, Nr4a2, Park2, Park7, and Snca), as well as the rare neurodegenerative disorder, Menkes disease (Atp7a) 5,6,10,11,12 . In Parkinson’s disease, it is thought that only in advanced stages of the disease do serotonergic nuclei degenerate, whereas earlier on in disease progression, there could be increases in serotonin function 13,14,15,16 . However, unanticipated changes in monoamine levels often exist in mouse models of Parkinson’s 21 .…”