Serotonin modulation of the basal ganglia circuitry: therapeutic implication for Parkinson's disease and other motor disorders
Introduction
Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a bewildering diversity of behavioural and physiological processes. This is not surprising, considering the almost ubiquitous distribution of 5-HT-containing axon terminals throughout the CNS, although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem. Despite this broad axon-terminal domain of 5-HT neurons, a closer examination reveals a preferential targeting of motor areas in the CNS (Steinbusch, 1981). For example, in the rat, there is a very dense innervation of the ventral horn of the spinal cord, the motor nucleus of the trigeminal, the facial motor nucleus and all components of the basal ganglia circuitry (Lavoie and Parent, 1990). It is thus likely that 5-HT plays a role in regulating the appropriate selection of voluntary movements by the basal ganglia, and abnormalities in 5-HT transmission might contribute to the neural mechanisms underlying disorders of basal ganglia origin, such as Parkinson's disease (PD), Tourette's syndrome and obsessive compulsive disorder (Chapter 24; Ring and Serra-Mestre, 2002). Indeed, biochemical evidence suggests that 5-HT transmission is abnormal in the basal ganglia of patients with PD (Hornykiewicz, 1998) and, moreover, in the movement abnormalities generally associated with the use of l-3,4-dihydroxyphenylalanine [levodopa (l-DOPA)] and classical antipsychotic drugs’ (APDs) motor side effects (Bezard et al., 2001; Blackburn, 2004; Di Giovanni et al., 2006a; Chapters 22 and 23 in this volume).
During the last decades, advances in the understanding of receptors mediating the effect of 5-HT have represented one of the success stories of neuropharmacology. Many of the 5-HT receptors are found within the basal ganglia and most likely involved in the modulation of basal ganglia circuitry and in the pathology of their correlated disorders. Of particular interest with respect to the development of new treatments for PD and other motor disorders are the 5-HT1A/1B and 5-HT2A/2C receptor subtypes. This will be the subject of further discussion in the remainder of this chapter. First, the 5-HT innervations of the basal ganglia and the distribution of 5-HT receptors throughout the various nuclei will be summarized. Thereafter, several aspects of 5-HT control of the pathophysiology of basal ganglia nuclei will be discussed.
Therefore, it is clear that a detailed understanding of the neurotransmitter function in each condition is not merely academic but can lead to a rationale for drug design and treatment strategies appropriate for that group of patients.
Section snippets
5-HT innervation of basal ganglia
More than 50 years have passed since Twarog and Page (1953) isolated an indole, identified as 5-HT, in the mammalian brain. Subsequently, Brodie et al. (1955) suggested that 5-HT might serve as a neurotransmitter in the CNS.
In vertebrates, the majority of the neurons containing 5-HT are grouped in nine nuclei named B1–B9, located in the medial part of the brain stem, generically called the raphe nuclei (Dahlström and Fuxe, 1964). These midline clusters can be divided into two major groups. The
5-HT receptors’ distribution within the basal ganglia nuclei
A vast amount of research has led to the discovery and characterization of a plethora of 5-HT receptor subtypes. At present, seven classes of 5-HT (5-HT1−7) receptors have been identified, which comprise at least 15 subtypes (Hoyer et al., 2002) (Table 1). This is not surprising, since with so many potential targets distributed throughout the CNS, 5-HT is a major neurotransmitter involved in such a large number of physiological and pathological processes.
The distribution of 5-HT receptors among
5-HT modulation of basal ganglia circuitry
The 5-HT modulation of DAergic nigrostriatal function, in terms of control of DA SNc neuron firing discharge and DA release in the striatum, has been extensively reviewed in Chapters 2 and 3. Therefore, we will not discuss this subject and we refer the readers to these two chapters.
Parkinson's disease
PD is the second most common neurodegenerative disease in the elderly population with an inevitable exitus. The idiopathic form is a progressive disorder, the impact of which reaches far beyond the clinical signs and symptoms exhibited by those afflicted. Clinical features at presentation include the asymmetric onset of cardinal motor symptoms such as tremor at rest, bradykinesia, muscular rigidity, stooped posture and instability (Sian et al., 1999).
Since Hornykiewicz's pioneering work in
Conclusions
From the large amount of literature reviewed here, it appears evident that the serotonergic neurotransmitter system plays a pivotal role in the modulation of basal ganglia circuitry (Fig. 1), and its dysfunction is involved in the pathophysiology of PD and other motor disorders.
Among all the 5-HT receptors present in the basal ganglia nuclei, the 5-HT1A/1B and 5-HT2A/2C receptors are particularly important, because of their localization and regulatory role on neurotransmitter release in many
Abbreviations
- 5-HIIA
5-hydroxy-indolacetic acid
- 5-HT
serotonin
- 5-HTT
5-HT transporter
- 6-OHDA
6-hydroxydopamine
- ACh
acetylcholine
- AHPs
after-hyperpolarizations
- APDs
antipsychotic drugs
- ATD
acute tryptophan depletion
- CNS
central nervous system
- DA
dopamine
- DBS
deep brain stimulation
- DRN
dorsal raphe nucleus
- EPN
entopeduncular nucleus
- EPS
extrapyramidal symptoms
- EPSCs
excitatory postsynaptic currents
- GLU
glutamate
- GP
globus pallidus
- GPe
external segment of the GP
- GPi
internal segment of the GP
- HFS
high-frequency stimulation
- IPSCs
inhibitory
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