Abstract
Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share similar pathophysiological mechanisms. From a neurochemical point of view, the serotonin (5-hydroxytryptamine; 5-HT) dysfunction in both movement disorders—related to probable lesioning of the raphe nuclei—is profound, and, therefore, may be partially responsible for motor as well as non-motor disturbances. More specifically, in ALS, it has been hypothesized that serotonergic denervation leads to loss of its inhibitory control on glutamate release, resulting into glutamate-induced neurotoxicity in lower and/or upper motor neurons, combined with a detrimental decrease of its facilitatory effects on glutamatergic motor neuron excitation. Both events then may eventually give rise to the well-known clinical motor phenotype. Similarly, disruption of the organized serotonergic control on complex mesencephalic dopaminergic connections between basal ganglia (BG) nuclei and across the BG-cortico-thalamic circuits, has shown to be closely involved in the onset of parkinsonian symptoms. Levodopa (L-DOPA) therapy in PD largely seems to confirm the influential role of 5-HT, since serotonergic rather than dopaminergic projections release L-DOPA-derived dopamine, particularly in extrastriatal regions, emphasizing the strongly interwoven interactions between both monoamine systems. Apart from its orchestrating function, the 5-HT system also exerts neuroprotective and anti-inflammatory effects. In line with this observation, emerging therapies have recently focused on boosting the serotonergic system in ALS and PD, which may provide novel rationale for treating these devastating conditions both on the disease-modifying, as well as symptomatic level.
Highlights
The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is produced in the raphe nuclei (RN), a moderately sized cluster of caudal and rostral neurons (B1-B9) found in the brainstem (Dahlstroem and Fuxe, 1964)
As for exacerbation of psychosis by L-DOPA treatment—attributed to excessive DA release in the mesolimbic areas rather than the motor striatum, mediated by hypersensitive 5-HT signaling—a favorable role for 5-HT2A receptor inverse agonists or 5HT2A antagonists has likewise been demonstrated (Cummings et al, 2013). These findings suggest that the serotonergic system may even adapt to the lack of DA by adopting anatomical and functional transformations in Parkinson’s disease (PD)
NA levels have been previously reported to be significantly increased in the cervical, thoracic and lumbar spinal cord of Amyotrophic lateral sclerosis (ALS) patients compared to controls (Bertel et al, 1991), with highest concentrations measured in ventral and intermediate gray matter
Summary
The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is produced in the raphe nuclei (RN), a moderately sized cluster of caudal and rostral neurons (B1-B9) found in the brainstem (Dahlstroem and Fuxe, 1964). The 5-HT1A receptor is expressed in the RN as a presynaptic autoreceptor, while it functions as a postsynaptic heteroreceptor in areas of the limbic system, such as the prefrontal cortex, hippocampus, lateral septum, and amygdala, as well as in (hypo)thalamus, and basal ganglia (Hoyer et al, 1994). Cerebral 5-HT2B receptors are present in the cerebellum, cerebral cortex, hypothalamus, corpus callosum and amygdala, causing anxiolytic effects among others (Duxon et al, 1997) This receptor subtype is likely to be expressed by RN neurons, where this autoreceptor might play a role in the regulation of the serotonin transporter (SERT) (Diaz et al, 2012). In PD and ALS, two invariably fatal neurodegenerative conditions, the motor and non-motor features have been partially attributed to disease-related malfunctioning of this overseeing neurotransmitter system
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