Review
Serotonin1B receptors: from protein to physiological function and behavior

https://doi.org/10.1016/j.neubiorev.2004.08.008Get rights and content

Abstract

The serotonin (5-HT)1B receptor is expressed in the central nervous system (CNS) of rodents and its homologous 5-HT1Dβ receptor is expressed in human. These receptors are distributed in both serotonergic and non-serotonergic neurons, where they act as auto- or heteroreceptors, respectively. Studies from ours and other laboratories have shown that 5-HT1B receptors are densely expressed in the ventral pallidum, globus pallidus, substantia nigra and dorsal subiculum and moderately expressed in the cerebral cortex, the molecular layer of the hippocampus, the entopeduncular nucleus, the superficial gray layer of the superior colliculus, the caudate putamen and the deep nuclei of the cerebellum. At the ultrastructural level, 5-HT1B receptors were found distributed in axons and axon terminals and these receptors are located on the plasma membrane of unmyelinated axon terminals and in the cytoplasm close to the plasmalemma. The terminal localization of the 5-HT1B receptors in CNS suggests that there is a signal responsible for the protein transport toward the nerve terminals. Studies from ours and other groups using lesion, radioligand binding sites, viral transfection and anterograde methods have shown that 5-HT1B receptors are located at the nerve terminals of different pathways. The 5-HT1B receptors act as terminal receptors and are involved in regulation of the release of various neurotransmitters, including 5-HT itself. The regulation of gamma-aminobutyric acid release by 5-HT1B receptors has been found in projections: from caudate putamen to the globus pallidus or substantia nigra, from nucleus accumbens to the ventral tegmentum area, and from purkinje neurons to the deep nuclei of the cerebellum. The control of glutamate release by 5-HT1B receptors has been found in projections from hippocampus to the dorsal subiculum and of N-acetyl-aspartyl-glutamate release from retinal ganglion cells to the superficial gray layer of the superior colliculus. The control of 5-HT release by 5-HT1B receptors was shown in projections arising from the raphe nuclei to fore- and midbrain regions. Multiple evidences suggest that 5-HT1B receptors are implicated in several physiological functions, behavior and psychiatric diseases including migraine, locomotor activity, drug abuse reinforcement, migraine, aggressive behavior, depression and anxiety states.

Introduction

Serotonin (5-HT) occupies an important place among the different types of neurotransmitters, as it intervenes in numerous physiological functions: appetite, thermoregulation, regulation of circadian rhythm, locomotor activity, sexual behavior, memory, vigilance, nociception, migraine; and in psychiatric diseases such as depression, anxiety and aggressivity. The cell bodies of serotonergic neurons (synthesized 5-HT) are localized principally in the cerebral trunk of the raphe nuclei and project to all cerebral regions [143], [185].

The multiplicity of physiological functions and behaviors that 5-HT participates in is linked, in part, to the large distribution of this neurotransmitter in the central (CNS) and peripheral (PNS) nervous systems and to the diversity of its receptors. More than 14 subtypes of 5-HT receptors have been determined by molecular and pharmacological techniques and classified following their patterns of distribution, coupling mechanisms and pharmacological profiles [16], [87]. Among these various 5-HT receptors, the 5-HT1B receptor has initially been claimed to exist only in rodents (rat, mouse and hamster) [82], [150], but subsequent cloning and sequencing studies have demonstrated that it is, in fact, the homologous species of the human 5-HT1Dβ receptor [3], [16], [83], [88]. There are few pharmacological differences to the distinction between the species variants of this receptor. For example, some β-adrenergic antagonists, such as (−)propranolol, bind 5-HT1B receptors in rodents with a much higher affinity than 5-HT1Dβ receptors in other species [3], [81]. These distinct pharmacological profiles are due to a single amino-acid difference (Asparagine versus Threonine) in the putative seventh transmembrane domain of the receptor [122], [140]. The same nomenclature is now recommended for this receptor in all mammalian species; the 5-HT1Dβ receptor in humans being renamed h5-HT1B, and the rat 5-HT1B receptor, r5-HT1B [83]. In this article, this receptor will be called the 5-HT1B receptor in rodent and 5-HT1Dβ receptor in human.

Serotonin1B receptors have been shown to be involved in several physiological functions, behaviors and psychiatric diseases including locomotor activity, drug abuse reinforcement, migraine, anxiety states and aggressive behavior [26], [62], [77], [95], [97], [125], [158], [169]. Numerous pharmacological studies have suggested that 5-HT1B receptors are expressed by both serotonergic and non-serotonergic neurons, acting as auto- and heteroreceptors, respectively, and regulating neurotransmitter release [59], [74], [113]. Previous findings from our studies and others showed that 5-HT1B receptors are located in the axon terminal on the plasma membrane of unmyelinated axons and in the cytoplasm close to the plasmalemma in different regions of the CNS [27], [162], [167], [168]. These findings provide anatomical support for the idea that 5-HT1B receptors act as terminal receptors and are involved in the pre-synaptic regulation of the release of neurotransmitters, including 5-HT.

This review article will be discussing the neurocircuitry and outcomes of the different pathways that 5-HT1B receptors are distributed upon and the implication of the release of these neurotransmitters in relation to their involvement in physiological functions, behavior and psychiatric diseases.

Section snippets

Molecular structure

The 5-HT1B receptor in rat and mouse is composed of 386 amino-acids [3], [110], [199], whereas the 5-HT1Dβ receptor is composed of 390 amino-acids in human [56], [81], [91], [196], [202]. These receptors coupled to a G protein, contain seven transmembrane domains [67], [86], [192]. There is a difference of 32 amino-acids between the two receptors, but only eight amino-acids are located in transmembrane domains which most likely constitute the binding sites of ligands [67], [86], [192]. There is

Regional distribution of 5-HT1B receptors

The 5-HT1B receptor binding sites have been detected by autoradiography using [125I]CYP as a radioligand in the presence of isoprenaline to block β-adrenergic sites [149]. High densities of 5-HT1B receptor binding sites were found in basal ganglia, particularly in the globus pallidus and substantia nigra. The distribution of the 5-HT1B receptor binding sites found in rat brain using [125I]GTI and [125I]CYP, was similar to that of the 5-HT1Dβ receptor binding sites observed in guinea pig and

Implication of 5-HT1B receptors in control of synaptic neurotransmission

Findings from ours and other groups are compatible with the idea that 5-HT1B receptors function as auto- and heteroreceptors and could be responsible for modulating neurotransmitter release at the nerve terminals (Fig. 4). The effect of 5-HT1B autoreceptors in 5-HT release has been demonstrated in studies using intracerebral microdialysis. Activation of 5-HT1B receptors by RU 24969 has been reported to inhibit the release of 5-HT in the hippocampus [23], [111], frontal cortex [180] and in the

Role of 5-HT1B receptors in physiological functions, behavior and psychiatric diseases

Multiple studies have suggested that 5-HT1B receptors are involved in several physiological functions, behaviors and psychiatric diseases: migraine, locomotor activity, drug abuse reinforcement, depression, anxiety states and aggressive-like behavior [13], [26], [42], [62], [77], [94], [95], [97], [105], [125], [137], [158], [169].

Conclusions and future directions

Studies using radioligand binding sites, in situ hybridization, lesions, viral transfection and immunocytochemistry have demonstrated that 5-HT1B receptors are localized at nerve terminals. The anatomical localization of 5-HT1B receptors at axon terminals in different cerebral pathways and the pharmacological studies suggest that 5-HT1B receptors act as inhibitors for neurotransmission release at nerve terminals. As given in an example in the substantia nigra area (Fig. 5), 5-HT1B receptors

Acknowledgements

I am very grateful to Drs Daniel Verge and Michel Hamon for their advices on the anatomical parts of this work. I would like also to thank Ms Marie Jeanne Brisorgueil for her technical assistance and Ms Michelle D. Werner for editing this manuscript.

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