Serotonin1B receptors: from protein to physiological function and behavior

Neuroscience and Biobehavioral Reviews 28 (2004) 565–582 www.elsevier.com/locate/neubiorev

Review

Serotonin1B receptors: from protein to physiological function and behavior Youssef Saria,b,* b

a Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 5035, Indianapolis, IN 46202, USA De´partement de Neurobiologie des Signaux Intercellulaires, Institut des Neurosciences, CNRS URA 1488, Universite´ Pierre et Marie Curie, Paris 6, France

Received 25 June 2004; revised 23 August 2004; accepted 26 August 2004

Abstract The serotonin (5-HT)1B receptor is expressed in the central nervous system (CNS) of rodents and its homologous 5-HT1Db 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. q 2004 Elsevier Ltd. All rights reserved. Keywords: Neurotransmitters; Lesion; Anxiety states; Aggressive behavior; Depression; Migraine; Locomotor activity; Drug abuse reinforcement

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 566 2. Molecular structure and signal transduction of 5-HT1B receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 2.1. Molecular structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 2.2. Addressing mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567 3. Distribution and circuitry of 5-HT1B receptors in CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568

* Address: Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS 5035, Indianapolis, IN 46202, USA. Tel.: C1 317 274 4934; fax: C1 317 278 2040. E-mail address: [email protected] 0149-7634/$ - see front matter q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2004.08.008

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3.1. Regional distribution of 5-HT1B receptors . . . . . . . . . . . . . . . . . . . 3.2. Subcellular localization of 5-HT1B receptors . . . . . . . . . . . . . . . . . 3.3. Serotonin1B receptors in different pathways and regions of the CNS 3.3.1. Striato-nigral pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.2. Raphe nuclei and raphe-nigral pathway . . . . . . . . . . . . . . 3.3.3. Retino-collicular pathway . . . . . . . . . . . . . . . . . . . . . . . . 3.3.4. Caudate putamen, globus pallidus and ventral pallidum . . . 3.3.5. Hippocampus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3.6. Cerebellum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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4. Implication of 5-HT1B receptors in control of synaptic neurotransmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572 5. Role of 5-HT1B receptors in physiological functions, behavior and psychiatric diseases 5.1. Involvement of 5-HT1B receptors in the modulation of anxiety states . . . . . . . . . 5.2. 5-HT1B receptors and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. 5-HT1B receptors and aggressive behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. 5-HT1B receptors and migraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5. 5-HT1B receptors and drug abuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.1. Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.2. Cocaine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6. 5-HT1B receptors and locomotor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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6. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577

1. 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-HT1Db receptor [3,16, 83,88]. There are few pharmacological differences to

the distinction between the species variants of this receptor. For example, some b-adrenergic antagonists, such as (K)propranolol, bind 5-HT1B receptors in rodents with a much higher affinity than 5-HT1Db 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-HT1Db 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-HT1Db 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].

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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.

2. Molecular structure and signal transduction of 5-HT1B receptors 2.1. Molecular structure The 5-HT1B receptor in rat and mouse is composed of 386 amino-acids [3,110,199], whereas the 5-HT1Db 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 also a pharmacological difference between these two receptors, which might be linked to the structural differences. However, the seventh transmembrane domain of the 5-HT1B receptor has an asparagine residue which has been suggested to play a role in the binding of b-adrenergic antagonists derived of pindolol [79]. The 5-HT1Db receptor has a low affinity to these b-adrenergic antagonists and this receptor contains a threonine residue in place of asparagine. The replacement of threonine 355 in a 5-HT1Db receptor by asparagine has demonstrated that this mutation is responsible for high affinities against b-blockade which are characteristic of 5-HT1B receptors [122,140,145]. These studies have demonstrated that the marked difference between the pharmacological profiles of 5-HT1B and 5-HT1Db receptors is due to one aminoacid.

2.2. Addressing mechanism The 5-HT1B receptors are predominantly found localized at the pre-synaptic level [22,27,162,167,168] and it is probable that the protein is synthesized in the cell body and then transported toward the axon terminal. The mechanism of protein transport has been investigated by several studies using hippocampal neurons, Madin-Darby canine kidney (MDCK II) epithelial cells, Lilly and Company canine kidney (LLC-PK1) epithelial cells and transgenic knockout mice for 5-HT 1B receptors [51,71,93,101]. Indeed,

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Dotti and Simons [57] suggested that epithelial cells and neurons share a common mechanism of protein targeting, with the apical domain being the equivalent of axons and the basolateral domain corresponding to the soma and dendrites, respectively. Previous studies showed that 5-HT1B receptors were localized in a Golgi-like intracellular compartment in LLC-PK1 cells [101]. In contrast, 5-HT1B receptors were localized intracellularly in vesicles at the apical surface in MDCK II cells [71]. The differential targeting between these two types of renal epithelial cells could be explained by the fact that there are distinct sorting mechanisms, as has been suggested in previous studies [37,78]. Ghavami et al. [71] have shown that viral transfection of 5-HT1B receptors in cultured hippocampal neurons demonstrated axonal and somatodendritic localizations of these receptors. The authors of this study suggested that the dendritic localization of axonal proteins could be caused by either detection problems due to the close proximity of axons and dendrites in culture or by the missorting of dendrites due to overexpression. Analysis using target chimera of 5-HT1B receptors in LLC-PK1 cells revealed that these receptors and the chimera containing their third intracellular domain were localized in the Golgi apparatus [51], suggesting that this domain was responsible for intra-Golgi sequestration. However, the cellular localization examined by confocal microscopy suggests that the third intracellular domain of the 5-HT1B receptor was responsible for its Golgi-like localization in transfected LLC-PK1 cells [51]. This domain, within the third intracytoplasmic loop of the 5-HT1B receptor, appears to act as an axonal targeting signal in hippocampal neurons [93]. Another specific targeting signal is the C-terminal portion (comprising the last two transmembrane and the cytoplasmic C-terminal domains) of the 5-HT1B receptors. The differential sorting of the 5-HT1B receptors has been established in vivo using transgenic mice. The authors designed a new strategy to express 5-HT1B receptors in the striatum of mice which are knockout for these receptors. The findings of these studies have demonstrated that 5-HT1B receptors were transported exclusively to the terminals of projecting striatal neurons in these mice, preferentially in axons projecting to the globus pallidus and substantia nigra [71]. The studies of 5-HT1B receptor signal transduction indicate that these receptors are coupled negatively to adenylyl cyclase because their activation by selective agonists induces a decrease in adenylyl cyclase activity, which is stimulated by forskolin [24,173]. In transfected cells, 5-HT1B receptors were found to be coupled negatively to adenylyl cyclase by an intermediate G protein type Gi or Go [80,110,176]. The alternative signal transduction mechanism could be mediated through mitogen-activated protein kinase (MAP-kinase). Moreover, recent study has shown the existence of coupling of

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5-HT1B receptor to the activation MAP-kinase signaling system [156].

3. Distribution and circuitry of 5-HT1B receptors in CNS 3.1. 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 b-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-HT1Db receptor binding sites observed in guinea pig and human, with a high density in globus pallidus, substantia nigra and dorsal subiculum [20,21,28,142,175,195]. The binding sites are also found with moderate density in entopeduncular nuclei, superficial gray layer of the superior colliculus and periaqueductal gray. The 5-HT1B receptor binding sites are also found lightly localized in cerebral cortex, amygdala, hypothalamus and the superior layer of dorsal horn of the spinal cord [33,149]. The distribution of 5-HT1B receptor binding sites described above has been confirmed by immunocytochemistry in studies from our laboratory [167,168]. Specific

anti-peptide antibodies directed against a selective portion (Val263–Lys287) of the rat 5-HT1B receptor protein have been produced and characterized in previous study from our collaborators [102]. High immunoreactivities of 5-HT1B receptors were found in globus pallidus (Fig. 1A), substantia nigra (Fig. 1B), ventral pallidum and dorsal subiculum [167,168]. However, 5-HT1B receptors were moderately expressed in the caudate putamen, molecular layer of the hippocampus, entopeduncular nucleus, periaqueductal gray, superficial gray layer of the superior colliculus and deep nuclei of the cerebellum [168]. Other structures, such as the thalamus and cerebral cortex, only lightly expressed the 5-HT1B receptors. The detection of 5-HT1B receptors perfectly matched the previous description of receptor sites bound by radioactive ligands [28,33,149,175]. The 5-HT1B receptor mRNA has been identified in the raphe nuclei, striatum, cerebellum (Purkinje cell layer), hippocampus (pyramidal cell layer of CA1), entorhinal and cingulated cortex (layer IV), subthalamic nucleus, retinal ganglion cells, olfactory tubercle and nucleus accumbens (Acb), but not in the substantia nigra or the globus pallidus [22,32,110,199]. The numerous mismatches between the respective distributions of the 5-HT1B receptor protein and its encoding mRNA suggest that the 5-HT1B receptors are mainly located at the nerve terminals [32]. Findings from our work showed that 5-HT1B receptor immunoreactivity is diffused within the neuropil in the globus pallidus (Fig. 1C), substantia nigra (Fig. 1D), ventral pallidum and dorsal

Fig. 1. Immunohistochemical visualization of 5-HT1B receptors in selected brain regions. At intermediate magnification: (A) caudate putamen and globus pallidus, (B) substantia nigra. Immunostaining in these three regions is diffused within the neuropil, and no immunoreactive perikarya can be found, as further evidenced at higher magnification (C) and (D), respectively. CPu, caudate putamen; GP, globus pallidus; SN, substantia nigra. Scale bars: (A, B)Z1.15 mm, (C, D)Z0.045 mm.

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subiculum [167,168], where no immunoreactive perikarya can be found. In contrast, a recent study showed that 5-HT1B receptor immunoreactivity was found in both neuronal cell bodies and their nerve fibers in the hypothalamus using a different 5-HT1B receptor antibody [109]. This finding is contradictory to our and other studies, which suggest that 5-HT1B receptors are located only in axons and axon terminals. It is very important to find out how it could be possible that only one region such as the hypothalamus expresses 5-HT1B receptors in cell bodies and fibers. Further investigations need to be developed to confirm these findings. 3.2. Subcellular localization of 5-HT1B receptors Studies using radioligand binding sites at the ultrastructural level have shown the existence of 5-HT1B receptors at nerve terminals with non-synaptic differentiation in the superficial gray layer of the superior colliculus [27]. This study was the first evidence showing terminal localization of 5-HT1B receptors in the collicular layer. The confirmation of these findings has been established in a study from our laboratory using immunocytochemistry. The 5-HT1B receptors detected with the immunogold technique appeared to be exclusively localized on axons and axon terminals in the rat superficial gray layer of the superior colliculus [166]. Studies from our laboratory have shown for the first time that the 5-HT1B receptors were also found to be exclusively associated with axons and axon terminals in the substantia nigra and globus pallidus [167,168]. Similar observations were made by other authors in the globus pallidus and the substantia nigra, providing direct anatomical support for the suggestion (derived from the comparison of in situ hybridization and binding sites of radioactive ligands data) that 5-HT1B receptors might be located in axon terminals [22]. In the three areas examined in our studies, the substantia nigra, the globus pallidus and the superficial gray layer of the superior colliculus, 5-HT1B receptor-like peroxidase immunoreactivity was found to be associated with the plasmalemma and close to the cytoplasm of axons and/or axon terminals [167,168]. Another common feature of peroxidase immunolabeling is the absence of the association of 5-HT1B receptor-like immunoreactivity with synaptic differentiations, which confirm the findings from the study described by other group [27]. Other study has shown that 5-HT1B receptors were preferentially associated with the plasmalemma of unmyelinated pre-terminal axons and were not found on axon terminals in both substantia nigra and globus pallidus [162]. The authors of this study used the same antibody as we have used in previous work [102], and we encountered the same problem when the tissue was perfused with 4% paraformaldehyde. Using this specific antibody, 5-HT1B receptors could be detected at the nerve terminals only if the concentration of paraformaldehyde used for animal perfusion was limited to 2%. In this case, immunocytochemical techniques may have limited

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accessibility of receptor antigenic sites in the plasma membrane and it is possible that the low amount of 5-HT1B receptors located at the nerve terminals is below the detection limit of the technique. At the ultrastructural level, we have noticed after examination with immunocytochemistry of the three regions described above that an immunolabeled preterminal axons were frequently found in the substantia nigra [167], whereas they were barely observed in the globus pallidus or the superficial gray layer of the superior colliculus. Second, immunolabeled unmyelinated axon terminals were apposed to both unlabeled axon terminals and distal dendrites in the substantia nigra and the superior colliculus, whereas they contacted preferentially large dendritic shafts in the globus pallidus [168]. The nature of target cells is probably responsible for these regional differences. 3.3. Serotonin1B receptors in different pathways and regions of the CNS 3.3.1. Striato-nigral pathway The experiments from our laboratory have been focused on determining the nature and the localization of 5-HT1B receptors of the striato-nigral pathway. Lesion and immunocytochemical studies have been performed to investigate these issues. Injection of kainic acid into the striatum, and the degeneration of intrinsic neurons induced by this acid have been studied [46,119]. The lesion of striatal neuron cell bodies was observed using the immunoreactivity for the glutamate decarboxylase (GAD) enzyme of gamma-aminobutyric acid (GABA) synthesis, a neurotransmitter, which appears on 95% of striatal neurons. Using immunocytochemistry for GAD, we showed a reduction of GAD-immunoreactivity in caudate putamen on the ipsilateral side of the lesion. The effect of the excitotoxic lesion was seen in the projection of the striatal neurons 3 weeks after kainic acid injections. The GADimmunoreactvity was decreased in the substantia nigra (Fig. 2B) as compared to the contralateral side (Fig. 2A). This effect is not due to the destruction of neurons in these regions, but more likely to the disappearance of axons and terminals of striatal neurons. In addition, a decrease in 5-HT1B receptor-immunoreactivity was also detected in substantia nigra on the ipsilateral side (Fig. 2D) as compared to contralateral side (Fig. 2C) using autoradiography with ligand [125I]CYP binding sites or autoradio-immunohistochemistry [168]. At the ultrastructural level, our lesion study has shown that after 5 days of intrastriatal injections of kainic acid (a period which allows the detection of terminals in a state of degeneration), the decrease of 5-HT1B receptors determined by immunocytochemistry was due only to the disappearance of terminals and not to the degenerating trans-synaptic sites in substantia nigra. Axonic terminals in the process of degeneration, enwrapped with glial

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Fig. 2. Effects of intrastriatal injections of kainic acid on GAD and 5-HT1B receptor immunoreactivities. A, B: Striatal lesions induce a decrease in the density of GAD immunoreacrtivity in substantia nigra at the ipsilateral site of intrastriatal injection (B). C, D: Decrease of 5-HT1B receptor immunoreactivity found in susbtantia nigra at ipsilateral site of striatal lesion. (D) SNc: substantia nigra contralateral site, SNi, substantia nigra ipsilateral site. Scale bars: (A–D)Z1.14 mm.

structures, showed evidence of the 5-HT1B receptorimmunoreactivity on the terminals of the striato-nigral pathway [166]. We have also shown that 5-HT1B receptorimmunoreactivity was associated with the plasma membrane and adjacent cytoplasm, as it was observed in normal terminals. These data clearly showed that the lesion of the striatum injected with kainic acid induced degeneration of the terminals of striatal neurons projecting into substantia nigra and that 5-HT1B receptors were found located in these terminals [166]. In addition, 5-HT1B receptor-immunoreactive non-degenerating axonic terminals were found on the ipsilateral side of the lesion. This could be explained by the fact that a few fractions of the terminals were not affected by the lesion, but most of those fibers were from afferents other than those coming from striatum. The terminal localization of 5-HT1B receptors in the striatonigral pathway has been confirmed by a study using transgenic mice where the 5-HT1B receptors were expressed predominantly in the striatum of these knockout mice for these receptors [71]. The knock-back in mice used a CamKII promoter which drives the epitope tagged 5-HT1B receptor. The results of this study demonstrated that the 5-HT1B receptors were transported to the axon terminals of striatal neurons projecting to substantia nigra. We have used another method to determine the terminal distribution of 5-HT1B receptors in the striato-nigral pathway, the radiolabeled amino-acid ([3H]Leucine) was injected into striatum and animals have been sacrificed after 2 days of recovery. The radiolabeled amino-acid was captured by intrinsic neurons and incorporated into the protein, and anterograde axonal transport toward the terminals was observed projecting from striatum to

substantia nigra (see Ref. [168]). The significance of this observation is that it demonstrated partially radiolabeled axonal pre-terminals that expressed 5-HT1B receptors, which indicated that 5-HT1B receptors are synthesized in striatum and transported toward the substantia nigra. Together, these findings demonstrate that 5-HT1B receptors are localized at the nerve terminals of the striato-nigral pathway. 3.3.2. Raphe nuclei and raphe-nigral pathway In raphe nuclei, the mRNA of 5-HT1B receptors is expressed in cell bodies and the receptors are located at the nerve terminals [22,58,199]. The binding sites of 5-HT1B receptors in raphe nuclei have been suggested to be present on nerve terminals of other projections, which contact the serotonergic cell bodies [22]. In addition, in the raphe nuclei there is a reciprocal influence which exists between serotonergic projection neurons and the GABAergic interneurons or afferents and these interactions may be mediated by 5-HT1B, 5-HT1A and GABA(A/B) receptors [10]. The presence of 5-HT1B receptors in the dorsal raphe nucleus has been found to decrease the local release of 5-HT upon activation [53,130,184]. Microdialysis study has shown that 5-HT1B receptor agonist, CP 93,129, decreases extracellular 5-HT levels in the dorsal and median raphe nuclei of the rat. This effect was prevented by 5-HT1B receptor antagonist, SB224289 [2]. There is a lower effect of 5-HT1B receptor agonist in the dorsal raphe nuclei as compared to the median raphe nuclei which might be due to different efficacy or density of 5-HT1B receptors in each nucleus. In addition, it has been shown that the output of

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5-HT in the dorsal raphe is under the control of 5-HT1D receptors rather than 5-HT1B receptors [53,84,153,154]. It is most likely that 5-HT1B receptors have differential roles in the dorsal and median raphe nuclei. Studies using 5-HT1B receptor knockout mice have shown that the firing of 5-HT neurons in the dorsal raphe nucleus is under an excitatory influence mediated by 5-HT1B receptors [60]. The role of 5-HT1B receptors in the control of serotonergic cell firing is controversial. Initial observations showed that 5-HT1B receptor agonists failed to alter spontaneous 5-HT cell firing in the dorsal raphe nucleus [153,182]. Nevertheless, other work has described situations where higher doses of 5-HT1B receptor agonists enhanced 5-HT cell firing in the dorsal raphe nucleus [60,84] and the median raphe nucleus [2,179]. In order to determine the terminal localization of 5-HT1B receptors in raphe-nigral pathway, injection of [3H]5-HT into the dorsal raphe nucleus has been performed. The radiolabeled 5-HT was uptake by serotonergic terminal fibers projecting to substantia nigra, the silver grains visualized by autoradiography demonstrated profiles of serotonergic nature (Fig. 3A and B). The co-localization of autoradiographic labeling and 5-HT 1B receptor

immunoreactivities demonstrate that serotonergic neurons express 5-HT1B autoreceptors at the Axon and nerve terminals (Fig. 3A and B). This result was expected because of the previously established implication of 5-HT1B receptors in the control of 5-HT neurotransmission on the projecting side [19,59,114]. The serotonergic fibers innervating the substantia nigra are originated from the mesencephalic raphe nuclei (dorsal and median) [45,90,194]. A small portion of axons and varicosities were found by autoradiography, expressing 5-HT1B receptors in substantia nigra and indicating a serotonergic nature. This observation is compatible with previous findings showing a decrease of binding sites for 5-HT1B receptors in substantia nigra after a lesion of the serotonergic system [197]. Together, these findings demonstrated that 5-HT1B receptors are localized at the nerve terminals of the raphe-nigral pathway.

Fig. 3. Double labeling of 5-HT1B receptors using immunocytochemistry and autoradiography, in the substantia nigra. (A, B) Silver grains (arrows) indicate the presence of radioactive material in axons (A, B) arising from the raphe nuclei, where [3H]5-HT was injected two hours before death. Immunoperoxidase labeling (arrowheads) reveals 5-HT1B receptors in axons. Ax, axon; T, terminal. Scale barsZ0.2 mm.

3.3.4. Caudate putamen, globus pallidus and ventral pallidum The caudate putamen nucleus is considered to be the only structure where high densities of mRNA and moderate binding sites for 5-HT1B receptors are found [22].

3.3.3. Retino-collicular pathway In the superficial gray layer of the superior colliculus, 28 days after an unilateral eye ablation, the density of 5-HT1B receptor binding sites was found to be reduced by 30% on the contralateral side of the lesion [25]. This finding confirms previous work from the same laboratory which suggested that 5-HT1 binding sites are located on retinal afferents in the rat superior colliculus [174]. At the ultrastructural level, eye ablation led to the lesion of the optic nerve followed by a degeneration of 5-HT1B receptorbearing axon terminals in the superficial gray layer of the superior colliculus on the deafferented (contralateral) side as shown by quantitative autoradiography [27]. The retinal deafferentation was associated with a 20–30% loss of 5-HT1B receptor binding sites [25] and the appearance of degenerating terminals labeled with [125I]GTI in the superficial gray layer of the superior colliculus [27]. This was a direct evidence of the existence of 5-HT1B receptors in visual afferents in non-synaptic contacts and in nonserotonergic terminals. Studies from our laboratory using immunocytochemistry technique have confirmed these findings, and our results indicate similarly that 5-HT1B receptors are present on nerve terminals of projecting retinal ganglion cells [166]. As expected from the moderate decrease of 5-HT1B receptor binding sites following enucleation, we also found immunolabeled axon terminals in the same area that were not affected by retinal deafferentation [166]. These terminals could belong to other 5-HT1B receptor-expressing afferent fibers and/or to projecting serotonergic neurons [27,129,198,201]. Findings from our and other studies have demonstrated that 5-HT1B receptors are localized at the nerve terminals of the retinocollicular pathway.

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This consideration agrees with our previous study, which demonstrated that 5-HT1B receptor-immunoreactivity was moderately higher in this structure (Fig. 1A). The lesion of the serotonergic system by 5,7-dihydroxytryptamine did not induce either a decrease [155,197] or an increase [139] of 5-HT1B receptor binding sites in striatum, suggesting that the receptors are located at the nerve terminals of other types of neurons such as glutamatergic or GABAergic neurons projecting toward the striatum. These findings suggest that the caudate putamen contains mostly 5-HT1B heteroreceptors located in these types of neurons (glutamatergic or GABAergic neurons). In the globus pallidus, 5-HT1B receptors are found located at terminals of the striato-pallidal pathway [168]. A study using 5-HT1B receptor knockout mice confirmed the fact that these receptors are transported along projections from the caudate putamen to the globus pallidus [71] which are GABAergic. The GABAergic fibers arising from the olfactory tubercle innervate the ventral pallidum; the olfactory tubercle expresses high levels of 5-HT1B receptor mRNA and low levels of binding sites [22]. The 5-HT1B receptors in the ventral pallidum might be located at the nerve terminals of the olfactory tubercle neurons, but the 5-HT1B receptor mRNA in the olfactory tubercle represents only a small fraction of GABAergic neurons and therefore demonstrates that the mRNA of 5-HT1B receptors must be expressed in other types of neurons [43]. 3.3.5. Hippocampus In the hippocampus, the pyramidal neurons of CA1 express high levels of the 5-HT1B receptor mRNA [199]. The interruption of the pyramidal CA1 axons and axon terminals unilaterally by stereotaxic knife cut induced a decrease in the density of binding sites for 5-HT1B receptors in the dorsal subiculum [5]. This is in accordance with previous studies suggesting that 5-HT1B receptors are localized predominantly on terminals of CA1 neurons projecting toward the dorsal subiculum [22,188]. In addition, studies using autoradiography for binding sites and immunocytochemistry have shown that the density of 5-HT1B receptors is higher in the dorsal subiculum [5,22,168]. Activation of 5-HT1B receptors in dorsal subiculum suppresses subicular transmission which might be suggested to affect the release of glutamate on nerve terminals arising from pyramidal cells of CA1 [15]. 3.3.6. Cerebellum In the cerebellum, high densities of the 5-HT1B receptor mRNA have been detected in the cell bodies of purkinje cells [110,199]. However, 5-HT1B receptor immunoreactivity [168], and autoradiography [149], was detected in deep nuclei of the cerebellum, which were receiving projections from these cells [22]. These observations suggest that the 5-HT1B receptors are localized on nerve terminals arising

from purkinje cells and these receptors are probably controlling the release of GABA at terminal levels.

4. 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 diencephalon [9]. Moreover, the 5-HT1B receptors function as heteroreceptors on non-serotonergic neurons. In vitro studies have shown an inhibitory effect of these receptors on acetylcholine release in rat hippocampus [38,113]. In the rat hippocampus, a study using synaptosomes labeled with [3H]choline has shown that cholinergic terminals in rat hippocampus possess 5-HT1B receptors, which upon activation, inhibit the release of acetycholine [113]. In addition, the investigation of fimbria-fornix lesions and intrahippocampal grafts of septal origins in the modulation of acetycholine release confirmed that cholinergic terminals possess muscarinic autoreceptors and 5-HT heteroreceptors of the 5-HT1B subtype [38]. The control of acetylcholine release by 5-HT1B receptors in septo-hippocampal pathway has been suggested to modulate anxiety states through nicotinic and muscarinic acetylcholine receptors located at the nerve terminals of this pathway [66]. Details for the implication of 5-HT1B receptors in anxiety states are addressed in the next chapter. Electrophysiological studies have also shown that activation of 5-HT1B receptors suppresses subicular transmission at low frequencies [15], these results suggest that activation of 5-HT1B receptors reduces the release of glutamate from incoming fibers originating from CA1 pyramidal cells to the subiculum, since this pathway was

Fig. 4. Schematic diagram of the circuitry of 5-HT1B receptors in CNS. 5HT1B receptors are located at the terminals of different pathways implicated in the release of neurotransmitters such as GABA, glutamate and 5-HT.

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considered to be glutamatergic. Therefore, activation of 5-HT1B receptors on CA1 pyramidal cell axons reduces hippocampal output to the subiculum, local CA1 feedback inhibition and local CA1 excitatory transmission [126]. However, physiological consequences of hippocampal 5-HT1B receptor activation have not yet been revealed. There is the possibility that 5-HT1B receptors in the hippocampus play a role in the serotonergic control of learning. Indeed, behavioral studies have demonstrated that 5-HT1B receptor agonists induce a learning deficit [34], whereas a 5-HT1B receptor antagonist enhances learning consolidation (for review, see Ref. [121]). The lesion of the optic projection in rat demonstrated by a previous study has shown that there is a decrease of N-acetyl-aspartyl-glutamate (NAAG) immunoreactivity in the superficial gray layer of the superior colliculus [127]. In addition, an electrophysiological study has shown that NAAG is released upon depolarization [193]. The presynaptic localization of 5-HT1B receptors suggests that these receptors may control the release of NAAG, which probably serves as a neurotransmitter in the optic tract [6,128]. The 5-HT1B receptors located at the retino-tectal pathway have been suggested to play a role in the elevation of the visual distractibility by modulating transmission release [26]. Spinous neurons constitute a major population of the striatum, and project toward the globus pallidus and substantia nigra [18,75,144]. These neurons are GABAergic and also express neuropeptides, particularly substance P and dynorphin for the population innervating the substantia nigra (see Ref. [70]). Activation of the 5-HT1B receptors in substantia nigra controls the release of GABA, as demonstrated by electrophysiological studies [92,183], and the presence of 5-HT1B receptor immunoreactivity on nerve terminals of GABAergic neurons is compatible with those findings. In the substantia nigra, GABA-containing terminals arising from the striatum are also thought to contact dendrites of GABAergic neurons, which in turn project to the thalamus and the superior colliculus (see Refs. [61,204]). The GABAergic terminals arising from the striatum constitute a major part of afferents contacting dendrites of dopaminergic neurons [17,181,200]. Some varicosities expressing 5-HT1B receptors are in contact with other immunonegative terminals, which form a characteristic arrangement ‘in a rosette’ around a dendrite (as observed in previous study [132]), in which case, the dendrite could be dopaminergic. As described in the present schematic representation, other terminals could be GABAergic and express the 5-HT1B receptors (Fig. 5). GABAergic neurons may control dopaminergic neurons via 5-HT1B receptors, as has been suggested by electrophysiological studies [95,183]. In addition, pre-synaptic inhibition of GABA release by 5-HT through 5-HT1B receptors is thought to indirectly stimulate neurons of the substantia nigra, whereas 5-HT could directly stimulate these neurons through the activation of 5-HT2C receptors as described by electrophysiological studies [164,183]. Further studies are

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Fig. 5. Schematic representation for electron micrograph of dopamine or GABA dendrite enwrapped by axonal varicosities. 5-HT-im and GABA-im axonal varicosities are in synaptic contact with GABA or dendritic dopamine. 5-HT1B receptors could be located at these GABAergic or serotonergic terminals as indicated by arrowheads. D, dendrite; T, terminal.

needed to investigate the precise relationships among serotonergic terminals; GABAergic terminals bearing 5-HT1B receptors, target dendrites containing dopamine, or GABA and/or other neurotransmitters in the substantia nigra. The findings may help clarify the role of 5-HT1B receptors in the nigral control of motor functions.

5. 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]. 5.1. Involvement of 5-HT1B receptors in the modulation of anxiety states Although it is not clear which receptor subtypes mediate the anxiogenic-like effects, 5-HT1A receptors have been the most extensively studied in this regard [49,65]. Findings from a number of clinical and animal studies suggest that the 5-HT1B receptors may also play a role in anxiety states [12,48,151]. The compounds used in earlier stages are considered to be partly selective for 5-HT1B receptors. Hence, no firm conclusions can be drawn from the data. Recent studies using selective 5-HT1B receptor agonists and antagonists provide more convincing evidence showing that activation of 5-HT1B receptors increases anxiety-like behavior [105]. The neuronal mechanism that underlies the anxiogeniclike effects of 5-HT1B receptor agonists is not clearly

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known, but several hypotheses can be proposed based on the neuroanatomical localization of this receptor and the neurophysiological consequences following its activation. The distribution of 5-HT1B receptors is heterogeneous in the CNS. These receptors control the release of several neurotransmitters and this fact alone accounts for their complex role in bringing about numerous neurophysiological changes. Current thinking in this field is that the modulation of anxiety states could involve several neuropathways in which 5-HT1B receptors are located at the nerve terminals, and it is likely that each pathway releases at least one type of neurotransmitter. Our work and the work of others have shown that 5-HT1B receptors are moderately expressed in the hippocampus and periaqueductal gray [33,168]. Activation of these 5-HT1B receptors has been shown to inhibit acetylcholine release in the hippocampus [113], and the primary source of cholinergic input to the hippocampus is the septum [44,108,120,131,186]. In evaluating the role of this pathway in anxiety-like behavior, it was found that activation of both nicotinic and muscarinic acetylcholine receptors produces anxiolytic-like effects, and antagonizing these receptors produces anxiogenic-like effects on the elevated plus-maze [66]. These findings suggest that tonic activation of these receptors plays a role in establishing baseline anxiety states. Thus, it is suggested that 5-HT1B receptors located at the nerve terminals of the septohippocampal pathway, may modulate anxiety states through the control of acetylcholine release. Another potential mechanism for regulating anxiety states may be the inhibitory modulation of GABA neurotransmission by 5-HT1B receptors [4,92]. GABAergic transmission manipulations in the dorsal periaqueductal gray have been shown to affect exploration on the elevated plus-maze [166], and 5-HT1B receptors have been suggested to be involved in anxiety states in this region [8]. The dorsal periaqueductal gray has reciprocal anatomical connections with the amygdala, and this pathway has been suggested to be GABAergic and may be involved in anxiety states [1,30,178]. Since 5-HT1B receptors have been found to modulate GABA transmission in the dorsal periaqueductal gray, we hypothesize that 5-HT1B receptors located at the nerve terminals of the amygdalo-periaqueductal gray pathway may modulate anxiety states through the control of GABA release. The modulation of anxiety states may also be under the control of dorsal raphe projections into the hippocampus, amygdala and dorsal periaqueductal gray, as 5-HT1B receptors located at the nerve terminals of these pathways may modulate 5-HT release. It has been suggested that the inhibition of the 5-HT1B autoreceptors [59,124] increases the release of 5-HT from nerve endings in the dorsal periaqueductal gray [8]. Previous studies demonstrated that viral-mediated overexpression of the 5-HT1B receptors in dorsal raphe nuclei increases anxiety-like behavior in animals after they have been exposed to stress and reduces

anxiety behavior in animals that not have been stressed [42]. It is important to note that 5-HT1B autoreceptors can also play a key role in anxiety behavior through the interaction with 5-HT1B heteroreceptors located particularly at the regions described above. Thus, we hypothesize that 5-HT1B autoreceptors modulate anxiety-like behavior through their control of 5-HT release and interaction with 5-HT1B heteroreceptors. 5.2. 5-HT1B receptors and depression The implication of 5-HT1B receptors in depression and in the action of antidepressant drugs is still unclear. Several studies have shown that chronic treatment to selective serotonin reuptake inhibitors (SSRIs) down-regulates and/or desensitizes 5-HT1B receptors [13,137] and facilitates the effect of SSRIs in 5-HT neurotransmission [52]. It has been suggested that SSRI antidepressant drugs act by downregulation of the serotonergic nerve terminal receptor. Thus, chronic treatment with SSRIs reduced the 5-HT1B mRNA in dorsal raphe nuclei and the effect is reversed after discontinuation of the drug [7,133]. In contrast, the 5-HT1B heteroreceptors are not found to be regulated by the SSRIs, as have been shown in frontal cortex, striatum and hippocampus [133]. Together, these studies suggest that chronic administration of antidepressant or SSRIs to rats, results in a down-regulation of 5-HT1B autoreceptors at the nerve terminal. Moreover, mice pretreated with 5-HT1B receptor antagonists showed increases in SSRI-induced effect [72,85,165] and this effect has also been observed in 5-HT1B receptor knockout mice [96]. However, the behavioral changes observed in 5-HT1B receptor knockout mice are inconsistent with the reports relative to wild-type mice, where SSRIs produce an enhanced response in 5-HT1B receptor knockout mice in the tail suspension test [116] and no effect was observed in the forced swimming test [191]. These evidences suggest that SSRIs combined with 5-HT1B receptor antagonists may produce a rapid antidepressant effect. It has been found that a long-term of blockade of 5-HT uptake may induce a desensitization of 5HT1B autoreceptors [13]. Together, these findings constitute very important evidence of the role of 5-HT1B autoreceptors in the facilitation of antidepressant-effects. A terminal 5HT1B autoreceptor antagonist or when it combine to SSRI may induce an increase of extracellular 5-HT levels in hyposerotonergic states and could be potentially useful in the treatment of depressive disorders resistant to therapy by using a single drug [31,112]. In humans, since all antidepressants may take 2–4 weeks to be effective, it would be essential to combine the antidepressant with a selective 5-HT1B receptor antagonist in order to shorten the period of treatment (see review of Briley and Moret, [31]). This would help to gain a rapid onset effect of antidepressants, rather than waiting for 2–4 weeks period for desensitization of the 5-HT1B autoreceptors.

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5.3. 5-HT1B receptors and aggressive behavior Studies of the neurochemical control of aggression in vertebrates, including humans, have indicated that high levels of serotonergic activity are associated with low levels of aggression [141,157,177,203]. This serotonergic inhibition of aggression seems to be mediated through interactions with several 5-HT receptor subtypes. Clear evidence for the involvement of 5-HT1B receptors in mediating aggression comes from transgenic mouse studies in which mice lacking 5-HT1B receptors are more aggressive than the wild-type mice [169]. Although these knockout mice may undergo adaptation during and after development, they are considered an interesting model for studying the function of 5-HT1B receptors. However, several issues should be taken in consideration of the use of 5-HT1B receptor knockout mice, as there are possibly other compensatory changes in addition to the lack of 5-HT1B receptor which could be involved in behavioral changes observed in these knockout mice. Numerous pharmacological studies have also suggested that the activation of 5-HT1B receptors reduces aggression. A non-selective agonist eltoprazine for 5-HT1A/1B/2C receptors reduces aggression in rats [172]. The selective 5-HT1B receptor agonists, CP 94253 and CGS 12066B, have also been shown to be capable of reducing very high levels of aggression which were in excess of species-typical norms [11,69]. Another drug with a 5-HT1B receptor agonist effect, anpirtoline, reduces aggression [123]. In addition, zolmitriptan, a 5-HT1B receptor agonist, exerted behaviorally specific anti-aggressive effects [54]. This latter study demonstrated that the anti-aggressive effects of zolmitriptan remained unaltered by 5,7-DHT lesions, which suggests that these effects are potentially due to the activation of 5-HT1B heteroreceptors since chemical lesioning of 5-HT axons did not prevent the effects. The findings of this study were in accordance with a previous study using 5,7-DHT lesions and treatment with eltoprazine, a non-selective 5-HT1B agonist, which showed anti-aggressive effects even after 5-HT axon lesions [177]. The mechanisms that implicate 5-HT1B heteroreceptors in aggression are still conflicting. Neurotoxic destruction of 5-HT neurons by 5,7-DHT often reduces aggression in mice and rats [64,177]. In addition, the neurotoxic lesions in mice spared approximately 20–40% of the ascending 5-HT neurons, and therefore we cannot completely eliminate the contribution of pre-synaptic sites to the anti-aggressive effects [54]. Previous studies have suggested that 5-HT might be acting through the 5-HT1B receptors, which inhibit aggressive responses [63]. The authors of this study have suggested that one area of the CNS that seems critical for the organization of aggressive behavior is the basolateral hypothalamus, particularly the anterior hypothalamic region. The neurochemical regulation of offensive aggression has been hypothesized by another study, which suggested that there is interaction between 5-HT and

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arginine vasopressin (AVP). 5-HT fibers originating from neurons in the raphe nuclei innervate populations of AVP neurons localized to the medial supraoptic nucleus and the nucleus circularis in the anterior hypothalamus [63]. These AVP neurons have been identified as potential sources of AVP innervation to the anterior hypothalamus and are potentially involved in aggressive behavior. 5.4. 5-HT1B receptors and migraine Serotonin plays an important role in the pathogenesis of migraine [99,159]. Several studies have shown a reduction of urinary and platelet 5-HT with elevations in 5-hydroxyindole acetic acid (5-HIAA) during migraine [50,100]. Furthermore, it has been suggested that there may be a deficiency of central 5-HT during migraine attacks and probably a compensatory super-sensitivity of central 5-HT receptors [73]. Among these receptors, 5-HT1B receptors were considered the preferred targets of modern antimigraine agents. It has been shown that the 5-HT1B receptors found localized in the endothelium of microvessels [163] may mediate vasodilatory and contractile effects depending upon their activation by circulating 5-HT release. The discovery of ergotamine and methysergide, which, like 5-HT itself, produces selective vasoconstriction of the carotid arterial bed through 5-HT1B receptors, profoundly stimulated migraine research [170] and led to the development of sumatriptan [89]. Sumatriptan, a 5-HT1B receptor agonist, inhibits the release of calcitonin-generelated peptide (CGRP), which acts in the superior sagittal sinus following stimulation of trigeminal ganglion [35]. This pre-synaptic inhibition of sensory fibers in the membrane of blood vessels might have a direct action on these vessels; vasoconstriction of dura-matter vessels which produces the anti-migraine effects of sumatriptan. Identification of molecular signaling events in migraine pathology and therapy has provided new insights into the pharmacology and signaling mechanisms of sumatriptan and related drugs, and may provide the foundation for the development of novel treatments for migraine. 5.5. 5-HT1B receptors and drug abuse Serotonin1B receptors have been implicated in drug abuse reinforcement. In the present review, I will focus on and discuss the abuse of alcohol and cocaine. 5.5.1. Alcohol Serotonin1B receptors have been studied and linked to the anti-social behaviors of alcoholics [103] and evidence suggests that these receptors are involved in many of the effects of alcohol. The administration of 5-HT1B receptor agonists decreases alcohol intake [115,189]. Furthermore, previous studies have shown that 5-HT1B receptor gene knockout mice consume more alcohol than wild-type mice

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and are more sensitive to some of the ataxic effects of alcohol [14,47]. The 5-HT1B receptor agonist CP-94,253 has been found to decrease the aggression-heightening effects of alcohol [69]. The physiological link between alcohol drinking and aggression has been documented in several studies, and after mice have been reinforced with a moderate dose of alcohol, they show increased attack and threatening behavior relative to their normal or baseline aggressive behavior [123]. The effects of alcohol on aggression are largely dependent on the amount of alcohol involved and the individual’s behavioral history and vulnerability. The 5-HT1B receptor agonist, zolmitriptan, was effective in mice that are highly aggressive after alcohol, which supports the suggestion that 5-HT1B receptors are of significance, presumably indirectly, in the aggressionheightening effects of alcohol [69]. The mechanism of involvement of 5-HT1B receptors in the self-administration of alcohol is unknown. A previous study demonstrated that 5-HT1B receptor binding sites were lower in the cingulated and retrospenial cortices, in the lateral and medial septum and in the lateral nucleus of the amygdala in the alcohol-preferring rats as compared to those of alcohol non-preferring rats [117]. The authors of this study postulated that the lower densities of 5-HT1B binding sites in the CNS of the alcohol-preferring rats may have been a result of reduced numbers of 5-HT1B autoreceptors as well as heteroreceptors. A lower density of 5-HT1B receptor binding sites was found also in Acb, olfactory tubercles and medial prefrontal cortex [118]. This suggests that the reduction of 5-HT1B receptor density or the reduction of receptor activities might predispose the animals to increase their alcohol consumption. Together, these findings suggested that both 5-HT1B auto- and heteroreceptors are involved in alcohol drinking. 5.5.2. Cocaine Serotonin1B receptors play a role in mediating the reinforcement of psychostimulant addiction. The activation of 5-HT1B receptors has been shown to induce potentiation and enhancement of some of the reinforcing properties of cocaine [146–148]. It has been demonstrated that 5-HT1B receptors mediate the cocaine-induced reduction of GABA release in the ventral tegmentum area (VTA) [36,138] and contribute to cocaine-induced striatal c-fos expression [107]. These findings are considered to be evidence of the involvement of 5-HT1B receptors in the physiological and behavioral effects produced by the use of cocaine. An acute pharmacological blockade of the 5-HT 1B receptors decreases some effects of cocaine, while constitutive genetic knockouts of the same receptors have the opposite effects [39]; these could be due to the compensatory changes that the knockout mice might undergo during their developing adult ages. The neural mechanisms via which 5-HT1B receptor agonists facilitate cocaine reinforcement are unknown and

there are many different hypotheses suggesting possible mechanisms. If the lesions of serotonergic neurons increase the reinforcing effects of cocaine [106], then it is possible that 5-HT1B receptor agonists such as RU 24969 and CP 94253 facilitate cocaine reward by reducing 5-HT release via 5-HT1B autoreceptor stimulation. A dual mechanism by which 5-HT1B receptors mediate the regulation of neurotransmitters is that 5-HT1B receptors may modulate the activity of dopamine neurons in the Acb. There are GABAergic neuron projections from Acb toward VTA where 5-HT1B receptors are located at their nerve terminals (Fig. 4) [68,98] and dopaminergic neuron projections from the VTA to the Acb [187]. Exposure to cocaine might lead the Acb and VTA neurons to undergo a variety of adaptations that could influence the sensitization and rewarding effects of cocaine [36,41,92,148]. Recent studies have indicated that increased expression of 5-HT1B receptors, using viral transfection of these receptors in Acb efferents (which are probably the terminals of neurons projecting to the VTA), increased cocaine-induced locomotor hyperactivity without affecting baseline locomotion [134]. In addition, both the Acb and VTA areas are receiving serotonergic projections [104,152]. Therefore, exposure to cocaine increases the extracellular concentrations of 5-HT and dopamine [29,147,160]. This suggests that both 5-HT1B auto- and heteroreceptors are implicated in the regulation of the addictive effects of cocaine. 5.6. 5-HT1B receptors and locomotor activity Evidence points towards 5-HT1B receptors playing a prominent role in the control of locomotor activity. The abundance of 5-HT1B receptors in motor control centers (the globus pallidus, substantia nigra and deep nuclei of cerebellum) (Fig. 4) [22,110,168], suggests their involvement in the control of locomotor activity. Activation of 5-HT1B receptor with either systemic or cerebral administration of RU 24969 (5-HT1B receptor agonist) results in a dose-dependent increase in locomotor activity [40,55,76]. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) induced locomotor hyperactivity is mediated by 5-HT1B receptors [161,171]. The behavioral effects of 5-HT1B receptor agonist RU 24969 and MDMA are similar. These effects have been inhibited by the administration of 5-HT1B receptor antagonists such as pindolol and propranolol. The RU 24969-induced hyperlocomotion in rats is unaffected by 5-HT synthesis inhibition [56] and amplified by the prior destruction of serotonergic nerves [135,136, 190]. This mechanism indicates that 5-HT1B heteroreceptors play a role in the nigral control of motor functions. 5-HT1B receptors can finely control the motor output of the basal ganglia (Fig. 4) by acting on the GABA projection neurons either directly or through the local release of dopamine by dopaminergic dendrites, just as it has been hypothesized in the schematic representation (Fig. 5).

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6. 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 control the release of 5-HT and GABA which in turn interact to stimulate the release of dopamine. Furthermore, the implication of 5-HT1B receptors in synaptic neurotransmission could lead to changes in physiological function, behaviors and psychiatric diseases. 5-HT1B receptors have been suggested to play a role in depression, anxiety states, aggressive-like behavior, migraine, drug abuse reinforcement and locomotor activity. The mechanism by which 5-HT1B receptors act within these paradigms is still unknown. Several hypotheses have been raised in this report, for example, in the case of anxiety states and aggressive behavior, there is a possibility that the interaction of 5-HT1B auto- and heteroreceptors controls neurotransmitter release in the different pathways which may modulate these behaviors. To investigate the role of 5-HT1B receptors in the modulation of anxiety states and aggressive behavior, it is possible to determine the neuropathways where 5-HT1B receptors located at the nerve terminals and the control of neurotransmitter release. The role of 5-HT1B auto- and heteroreceptors in the modulation of such behavior can be determined by directly targeting 5-HT1B receptor gene expression with antisense oligodesoxynucleotides into putative sites. The organization of integrative pathways expressing 5-HT1B receptors could play an important role in the modulation of anxiety states and the control of aggressive behavior. Similar experimental designs would be applicable to investigate the mechanism by which 5-HT1B receptors act in the control of depression and drug abuse reinforcement. The results of the perspectives studies would provide pertinent information about the involvement of 5-HT1B receptors in psychiatric diseases. This knowledge needed to help design novel therapeutic approaches for the treatment of psychiatric diseases related to 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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