Serotonin modulation of the basal ganglia circuitry : therapeutic implication for Parkinson’s disease and other motor disorders

Several recent studies have emphasized a crucial role for the interactions between serotonergic and dopaminergic systems in movement control and the pathophysiology of basal ganglia. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of all the basal ganglia nuclei. In fact, serotonergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. In this chapter, the distribution of different 5-HT receptor subtypes in the basal ganglia nuclei will be described. Furthermore, evidence demonstrating the serotonergic control of basal ganglia activity will be reviewed and the contribution of the different 5-HT receptor subtypes examined. The new avenues that the increasing knowledge of 5-HT in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. It is clear that these avenues will be fruitful, despite the disappointing results so far obtained by clinical studies with selective 5-HT ligands. Nevertheless, these studies have led to a great increase in the attention given to the neurotransmitters of the basal ganglia and their connections.peer-reviewe

Serotonin Receptors in Hippocampus

Serotonin is an ancient molecular signal and a recognized neurotransmitter brainwide distributed with particular presence in hippocampus. Almost all serotonin receptor subtypes are expressed in hippocampus, which implicates an intricate modulating system, considering that they can be localized as autosynaptic, presynaptic, and postsynaptic receptors, even colocalized within the same cell and being target of homo- and heterodimerization. Neurons and glia, including immune cells, integrate a functional network that uses several serotonin receptors to regulate their roles in this particular part of the limbic system

5-Hydroxytryptamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

oai:ojs.pkp.sfu.ca:article/31555-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [194] and subsequently revised [176]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [40, 482]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [463, 382])

5-Hydroxytryptamine receptors in GtoPdb v.2023.1

5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [198] and subsequently revised [180]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [40, 491]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [471, 387])

Serotonin and the CNS

Serotonin is an ancient neurotransmitter system involved in various systems and functions in the body and plays an important role in health and disease. The present volume illustrates the broadness of the involvement of serotonergic activity in many processes, focusing particularly on disorders of the brain, including depression, stress and fear, Alzheimer’s disease, aggression, sexual behavior, and neuro-immune disorders. Chapters illustrate techniques and methods used to study the complex role of the serotonergic system in all kinds of processes, present new hypotheses for several brain disorders like sleep and depression, and use mathematical modeling as a tool to advance knowledge of the extremely complex brain and body processes

Drugs Affecting 5-HT Systems

Seminar transcriptIt was in the very early hours of a February morning in 1977 that I first looked down the microscope and saw yellow fluorescence, characteristic of 5-hydroxytryptamine (5-HT) in frozen sections of Octopus brain. After struggling for two years with the capricious fluorescence histochemical technique to locate catecholamines and 5-HT, I finally had a successful result, and the PhD that had seemed a remote possibility for many months finally began to look feasible. Given the enormously important topic of this volume – the discovery and development of drugs affecting 5-HT systems – this small excursion into Octopus neurochemistry might seem irrelevant. However, cephalopod molluscs have played important roles in the history of 5-HT. More than 30000 pairs of posterior salivary glands of Octopus vulgaris were used by Vittorio Erspamer, for the first extraction and identification of enteramine, which was later shown to be identical to serotonin discovered by John Gaddum, and chemically characterized as 5-hydroxytryptamine. Other molluscs have provided some of the most sensitive bioassays for 5-HT, as Gaddum and Paasonen described in 1955, and several participants in this Witness Seminar recollected either using such bioassays or investigating invertebrate pharmacology at the beginning of their careers. Many reflected, however, that invertebrate receptors seemed to be very different from those found in mammals; they had, as David Wallis put it, ‘a parallel pharmacology’. One Witness, Merton Sandler, remembered attending a lecture by Vittorio Erspamer in London in the early 1950s, and being intrigued enough to start work on the degradative enzyme monoamine oxidase, a field which became highly significant for the development of a whole class of therapeutic drugs: the monoamine oxidase inhibitor

Brain serotonergic circuitries

Brain serotonergic circuitries interact with other neurotransmitter systems on a multitude of different molecular levels. In humans, as in other mammalian species, serotonin (5-HT) plays a modulatory role in almost every physiological function. Furthermore, serotonergic dysfunction is thought to be implicated in several psychiatric and neurodegenerative disorders. We describe the neuroanatomy and neurochemistry of brain serotonergic circuitries. The contribution of emergent in vivo imaging methods to the regional localization of binding site receptors and certain aspects of their functional connectivity in correlation to behavior is also discussed. 5-HT cell bodies, mainly localized in the raphe nuclei, send axons to almost every brain region. It is argued that the specificity of the local chemocommunication between 5-HT and other neuronal elements mainly depends on mechanisms regulating the extracellular concentration of 5-HT, the diversity of high-affinity membrane receptors, and their specific transduction modalities

Central serotonergic control of cardiovascular reflexes.

Central serotonergic neurones control reflex parasympathetic outflow to the heart, airways and bladder in a number of species, and different 5-HT receptor subtypes are involved in this effect. 5-HTiA and 5-HT3 receptors in the brainstem facilitate these reflexes, whilst 5-HTiB/id, 5-HT2 and 5-HT4 receptors inhibit them. Recently, central 5-HT7 receptors have been implicated in bladder reflexes. Experiments on anaesthetised rats showed that the selective 5-HT7 receptor antagonists SB-269970 and SB-656104, given intracisternally (i.e.), attenuated cardiopulmonary, baroreflex and chemoreflex bradycardias. Similarly, the selective 5-HTia receptor antagonist WAY-100635 attenuated cardiopulmonary and chemoreflex (but not baroreflex) bradycardia, whilst robalzotan and (-)-pindolol (antagonists at 5-HTiA receptors) had no effect on cardiopulmonary and baroreflex bradycardias respectively. Chemical stimulation of presumed serotonergic cell bodies in raphe magnus/pallidus evoked a bradycardia that could not be attenuated either by 5-HT receptor antagonists (given i.v.) or by prior 5-HT depletion. The latter did, however, significantly attenuate cardiovascular reflex sensitivity. Activation of nucleus tractus solitarius (NTS) neurones by the vagus was inhibited by the iontophoretic AMP A receptor antagonist DNQX or by topical SB-269970. Subsequent histology suggested that 5-HT containing terminals do not make close appositions with these neurones. Preliminary data demonstrate that SB-269970 (given i.e.) effectively attenuates the cardiopulmonary reflex in awake rats, but has variable effects on the chemoreflex. The data suggest that 5-HT7 receptors in the NTS are crucially involved in the central transmission of reflex bradycardias, at least in rats. The role of the 5-HTia receptor is less clear-cut than in the rabbit, and may reveal a species difference. The origin of 5-HT activating these receptors is unlikely to be the medullary raphe neurones, but may be primary afferents terminating in the NTS. Since recent ultrastructural evidence shows 5-HT terminals and NTS cardiovascular neurones are often separated by astroglial leaflets, astrocytes may be involved in serotonergic-glutamatergic signalling

Neuronal localization of the 5-HT2 receptor family in the amygdaloid complex

The amygdaloid complex (or amygdala), a heterogeneous structure located in the medial portion of the temporal lobe, is composed of deep, superficial, and “remaining” nuclei. This structure is involved in the generation of emotional behavior, in the formation of emotional memories and in the modulation of the consolidation of explicit memories for emotionally arousing events. The serotoninergic fibers originating in the dorsal and medial raphe nuclei are critically involved in amygdalar functions. Serotonin (5-hydroxytryptamine, 5-HT) regulates amygdalar activity through the activation of the 5-HT2 receptor family, which includes three receptor subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. The distribution and the functional activity of the 5-HT2 receptor family has been studied more extensively than that of the 5-HT2A receptor subtypes, especially in the deep nuclei. In these nuclei, the 5-HT2A receptor is expressed on both pyramidal and non-pyramidal neurons, and could play a critical role in the formation of emotional memories. However, the exact role of the 5-HT2A receptor subtypes, as well as that of the 5-HT2B and 5-HT2C receptor subtypes, in the modulation of the amygdalar microcircuits requires additional study. The present review reports data concerning the distribution and the functional roles of the 5-HT2 receptor family in the amygdal