I. Introduction

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The existence of an endogenous vasoconstrictor in blood serum (Stevens and Lee, 1984; Brodie, 1900) and the presence in the gut of a substance that increases intestinal motility (Vialli and Ersparmer, 1933) had been known to scientists since the beginning of the century. However, it was not until the serum vasoconstrictor was identified as 5-hydroxytryptamine (5-HT)² (Rapport et al., 1948) that it became clear that this amine was also present in the mammalian central nervous system (CNS) (Twarog and Page, 1953). Shortly after its discovery in the CNS, and based on the observation that it was heterogeneously distributed in the dog brain (Bogdansky et al., 1956), 5-HT was considered for the first time a putative neurotransmitter in the CNS. A major turning point in 5-HT neurotransmission research then came about when Fuxe and Dahlström, using Falck-Hillarp histochemical fluorescence, provided the first description of 5-HT neurons (Dahlström and Fuxe, 1964) and their projections (Fuxe, 1965). Today, it is an established fact that no region in the mammalian CNS lacks 5-HT innervation (Dahlström and Fuxe, 1964; Steinbusch, 1981, 1984; see Azmitia, 1986; Jacobs and Azmitia, 1992; Azmitia-Whitaker and Azmitia, 1995).

As a neurotransmitter, the ubiquity of 5-HT is not only anatomical but also phylogenetic. Having been identified in neurons of the cnidarian Renilla koellikeri (Umbriaco et al., 1990), it could be one of the most ancient of currently known transmitters. From primates (see Azmitia and Gannon, 1986; Törk, 1990) to Chondrichtyes (Stuesse and Cruce, 1992), the adult 5-HT system is organized into two subsystems, i.e., a rostral division with cell bodies localized in the midbrain and rostral pons, providing projections to the forebrain, and a caudal division located primarily in the medulla oblongata with descending projections to the spinal cord and brainstem nuclei. Similarities found among such divergent vertebrate brains indicate that the major nuclear organization and the 5-HT projection network have remained remarkably stable across phylogeny. In spite of its remarkable evolutionary stability (Jacobowitz and MacLean, 1978), careful scrutiny of comparative anatomical evidence indicates that differences are as important as similarities. These phylogenetic differences may be summarized as follows: in higher mammals the system has evolved toward a fast, precise type of neurotransmission in which 5-HT neurons give rise to few collaterals (Fallon and Loughlin, 1982), have a high proportion of myelinated axons, and, due to the existence of a high proportion of junctional synapses, terminal field innervation is localized. In lower mammals the system is diffuse, highly branched, unmyelinated, and nonjunctional innervation predominates in terminal fields (see Azmitia 1986; Descarries et al., 1990; Törk, 1990; Jacobs and Azmitia, 1992; Azmitia and Whitaker-Azmitia, 1995).

Because 5-HT neurons are among the first neuroblasts to differentiate, the 5-HT system is also ontogenically ancient. Indeed, in the rat brain 5-HT-immunoreactivity appears as early as gestational day 12 (Olsen and Seiger, 1972; Lidov and Molliver, 1982), tryptophan hydroxylase activity is present at fertilization, and nearly every embryonic cell contains 5-HT until the gastrula stage (Harris, 1981). The first 5-HT neurons appear in early development and are located rostrally, within the mesencephalon (Lidov and Molliver, 1982) Two days later, a more caudal rhombencephalic group appears (Wallace and Lauder, 1983). In the next sections, focus will be on the rostral group.

	II. Morphological Aspects of the 5-HT Rostral System

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Dahlström and Fuxe (1964) divided 5-HT cell clusters into nine groups (B_1-9), B₁ being the most caudal group of cells. Today, however, the nomenclature most frequently used refers to 5-HT cells contained within cytoarchitectonic brainstem entities known as the raphe nuclei. Rostral 5-HT neurons are not confined to midline (raphe) nuclei, they are also present in more lateralized sites of the reticular formation, especially 1) dorsal to the medial lemniscus (rat: Dahlström and Fuxe, 1964; Baker et al., 1990) and 2) dorsal to the nucleus raphe pontis oralis (Lidov and Molliver, 1982; Baker et al., 1991).

1. The Caudal Linear Nucleus. The caudal linear nucleus (CLN), described in primates by Törk (1990) and Azmitia (see Azmitia, 1986; Azmitia and Gannon, 1986; Jacobs and Azmitia, 1992; Azmitia and Whitaker-Azmitia, 1995), is the most rostral group of serotonergic neurons in the mesencephalic midline, extending along the rostral boundary of the superior cerebellar decussation. Its ventral limit is defined by the interpeduncular nucleus and dorsally it contacts the dorsal raphe nucleus (DRN) through the gap left between the two medial longitudinal fasciculi. In rats, 5-HT neurons located rostral to the decussation of the superior cerebellar peduncle and above the interpeduncular nucleus have been considered in some cases a rostral extension of the median raphe nucleus (MRN) (Lorez et al., 1978; Parent et al., 1981). However, CLN and MRN neurons do not share common terminal projection fields (Imai et al., 1986) and display dissimilar dendritic morphology (Hornung and Fristchy, 1988). On the other hand, because DRN and CLN 5-HT neurons innervate similar terminal fields (e.g., caudate-putamen in adult rat brain; Imai et al., 1986) and share a common developmental origin (Wallace and Lauder, 1983), an alternative approach proposes that CLN neurons should be considered similar to those in DRN (see Jacobs and Azmitia, 1992).

2. The Dorsal Raphe Nucleus. The DRN is the largest of the brainstem serotonergic nuclei containing about 50% of 5-HT neurons in the rat CNS (Wiklund and Björklund, 1980; Descarries et al., 1982), 40% in the cat CNS (Wiklund et al., 1981), and 50 to 60% in the human CNS (Baker et al., 1990). Rostrally, the dorsal raphe is bound by the Edingher Westphal nucleus (III) and, caudally, it extends just ventral to the confluence of the fourth ventricle and the cerebral aqueduct (Steinbusch, 1981; Descarries et al., 1982; Imai et al., 1986; Törk, 1990; Jacobs and Azmitia; 1992). In most species, the DRN is composed of several subregions distinguished by their different cell density, morphology, and projections (Azmitia and Gannon, 1986; Baker et al., 1991; Johnson and Ma, 1993): 1) a medial portion, subdivided in turn into dorsomedial and ventromedial components, just below the cerebral aqueduct and surrounding the medial longitudinal fasciculus (MLF), respectively; 2) lateral portions or wings (much more prominent in primates than other mammals due to a lateralization process through phylogeny; Descarries et al., 1982; Azmitia and Gannon, 1986; Baker et al., 1991); and 3) a caudal component. During development (15 days of gestation), 5-HT-immunoreactive cells group themselves into two different clusters, dorsolateral and ventrolateral to the MLF (Wallace and Lauder, 1983). The dorsolateral portion will give rise to the lateral wings of the DRN, whereas the ventrolateral group will split to form the interfascicular portion of DRN and MRN. For this reason, it has been proposed that, in the primate CNS (see Jacobs and Azmitia, 1992; Azmitia and Whitaker-Azmitia, 1995), the interfascicular subregion of the DRN should be best considered an entity along with the MRN. Olzewski and Baxter (1954) had previously defined an anatomical entity, nucleus centralis superior, consisting of three groups of cells: 1) a dorsalis component situated between MLF, 2) a medialis component or MRN, and 3) a lateralis component which includes the 5-HT cells that form the ring around the nucleus reticularis pontis oralis (see Table 1). The absence of anatomical boundaries between the main rostral portion of the DRN (B₇) and the main rostral portion of the MRN (B₈) has also been observed in rats (Descarries et al., 1982) and cats (Wiklund et al., 1981). The main rostral component of the DRN (B₇) also merges, in its rear end, with the caudal component (B₆) of this same nucleus (see Jacobs and Azmitia, 1992; Azmitia and Whitaker-Azmitia, 1995). Furthermore, the latter caudal component is in continuity with the dorsocaudal portion of the MRN (see Jacobs and Azmitia, 1992; Azmitia and Whitaker-Azmitia, 1995) and the lateral wings of the DRN (Lidov and Molliver, 1982). Hence, anatomical proximity between different 5-HT cell clusters provides the ground for a network of homotypic interconnections among 5-HT neurons. Such interconnections constitute in turn the morphological ground for the high degree of cross-talk existing among 5-HT neurons at the somatodendritic level. The major implication underlying this arrangement is that the more closely knit and the larger the number of cells in a functional cluster, the more powerful will be the effect of the group on the target structure toward which it projects (Azmitia, 1986).

3. The Median Raphe Nucleus. The MRN consists of two distinct parts, i.e., a group of densely packed cells, vertically oriented and concentrated in the midline, and a second group, the paramedian columns, consisting of cells scattered in the periphery of the midline cluster (Köhler and Steinbusch, 1982). The nucleus is situated ventral to the MLF and has a rostrocaudal oblique orientation (Azmitia, 1981; Lidov and Molliver, 1982). In its rostral end, beyond the MLF, it is separated from the DRN in its rostral end by the superior cerebellar peduncle decussation. Its medial portion extends from the mesencephalic interpeduncular nucleus to the trapezoid body in the pons. Laterally, the limits of the nucleus are poorly defined toward the reticular formation (Köhler and Steinbusch, 1982), and in the rat the MRN merges laterally with the 5-HT group in nucleus raphe pontis oralis (Lidov and Molliver, 1982). The MRN forms the second largest cluster of 5-HT neurons in the mammalian CNS (Baker et al., 1990).

4. The Supralemniscal Region. The last group of 5-HT neurons to be considered corresponds to 5-HT cells in the supralemniscal region. In the rat, 5-HT cells belonging to this group are scattered along the dorsal border of the medial lemniscus and extend their dendrites in between the fiber bundles of the latter (Parent et al., 1981; Steinbusch, 1981). A similarity between supralemniscal 5-HT cells and those of the MRN was first noted by Dahlström and Fuxe (1964) in the rat CNS and has been later confirmed in primates (Hubbard and Di Carlo, 1974). In fact, the cells in the supralemniscal region may be continuous with those of the paramedian columns of the MRN (Azmitia and Gannon, 1986). Unlike rodents in which the supralemniscal cell cluster is predominantly mesencephalic, in humans it is entirely located in the pons (Baker et al., 1991).

In all species studied thus far, neurons containing 5-HT consist of a morphologically heterogeneous population (Steinbusch, 1981; Jacobs et al., 1984; Azmitia and Gannon, 1986; Törk and Hornung, 1990). The average cell diameter varies between 15 and 25 µm (Azmitia, 1978; Descarries et al., 1982), and, ultrastructurally, "5-HT specificity does not closely correlate with any particular neuronal configuration and/or intracellular build-up" (Descarries et al., 1982). No unique element allows to distinguish 5-HT cell bodies from non-5-HT surrounding neurons.

The average number of axosomatic boutons received by 5-HT neuron perikarya in the DRN has been quantified by Descarries et al. (1982). Although 100 µm of somatic membrane receive seven axonic boutons, the average number of spines on the same membrane length is 2.7 (Park et al., 1982). On the dendrites, the number of axonic boutons per 100-µm membrane length is roughly 60% higher than on the soma (Descarries et al., 1982). In cats and rats, the fibers contributing to these axosomatic or axodendritic contacts are non-5-HT fibers (Descarries et al., 1982; Chazal and Ralston, 1987). In primates, Kapadia et al. (1985) have described 5-HT fibers impinging on 5-HT dendrites.

1. Sources of Extracellular 5-HT in Rostral Raphe Nuclei The existence of serotonergic axon terminals in the raphe nuclei of cats and rats has been repeatedly reported (Baraban and Aghajanian, 1981; Chan-Palay, 1982; Descarries et al., 1982; Chazal and Ralston, 1987), but the terminals endowed with synaptic specializations have been found to be consistently in low numbers, ranging from "none" (Baraban and Aghajanian, 1981), "exceedingly small number" (Descarries et al., 1982), to "a few" (Chazal and Ralston, 1987). Furthermore, Baraban and Aghajanian (1981) found 5-HT fibers exclusively in axon bundles rather than in proximity to dendrites or cell bodies, and when 5-HT terminals were observed to make somatodendritic synaptic contacts, these were on non-5-HT neurons (Descarries et al., 1982; Chazal and Ralston, 1987). In the rare cases in which a 5-HT axon terminal was observed in close apposition to a 5-HT cell body, no demonstrable synaptic contact was present (Chazal and Ralston, 1987). Nonsynaptic 5-HT axon terminals are not exclusive to the raphe nuclei; they also exist in projection areas such as the cortex, striatum, and hippocampus (Descarries et al., 1990; Törk, 1990). 5-HT release therefore occurs not only from junctional but also from nonjunctional sites (Descarries et al., 1975, 1982, 1990).

2. Cell Bodies Found in the 5-HT Nuclei. Quantitative studies of the total number of 5-HT neurons located in the ascending raphe nuclei indicate that there are about 288,000 in the human brain (Törk, 1990), 33,000 in the cat brain (Wiklund et al., 1981), and 15,200 in the rat brain (see Jacobs and Azmitia, 1992). Moreover, 5-HT neurons represent but a small percentage of the total neuronal population of the raphe nuclei. Using histofluorescence-imaging techniques, Wiklund et al. (1981) reported that in the cat 5-HT neurons constitute 70% of medium-sized cells in the dorsal raphe and 35% of medium-sized neurons of the MRN. This percentage could be lower, serotonergic cells constituting 25 to 50% of the total DRN neuronal population and 20 to 30% of the MRN's. In the supralemniscal 5-HT cell group (B₉), the percentage of 5-HT neurons appears to be much lower than in the other two nuclei (O'Hearn and Molliver, 1984).

Afferent connections to the raphe nuclei have been studied using multiple techniques such as lesion and axon degeneration, histofluorescence, anterograde/retrograde tracer injection, autoradiography, and immunohistochemistry (Brodal et al., 1960; Fuxe, 1965; Aghajanian and Wang, 1977; Mosko et al., 1977; Sakai et al., 1977; Baraban and Aghajanian, 1981; Kalen et al., 1985; Stratford and Wirtshafter, 1988; Marzienkiewicz et al., 1989; Behzadi et al., 1990). Results from such studies have been summarized in Table 2.

Interconnections among raphe nuclei using retrograde-tracing techniques suggest a moderate-to-high density of 5-HT input. These observations contrast with those from most of the immunocytochemical or radioautographic ultrastructural studies indicating a low number of 5-HT fibers in the rostral raphe. Mosko et al. (1977) have reported that the main source of 5-HT fibers reaching the DRN arise either from the DRN itself or the MRN. The latter input has been confirmed by other groups (Sakai et al., 1977; Aghajanian and Wang, 1977; Kalen et al., 1985; Vertes and Kocsis, 1994). However, given the proximity between injection and labeled sites, it cannot be ruled out that tissue damage and tracer diffusion may account for part of the retrograde staining observed in the MRN after tracer injection into the DRN. Furthermore, since retrograde transport of horseradish peroxidase by dendrites has been reported (Smith et al., 1974), this raises the possibility that the accumulation of tracer by dorsal and median raphe perikarya resulted from retrograde transport by dendrites, rather than the axon terminals of these neurons. On the other hand, tracer diffusion or retrograde dendrite transport cannot account for the projections arising from more distant nuclei (Sakai et al., 1977; Kalen et al., 1985; Marzienkiewicz et al., 1989; Behzadi et al., 1990). Histochemical confirmation of the neurotransmitter contained in connections among 5-HT nuclei has been performed on rare occasions (Stratford and Wirtshafter, 1988), and when done, numerous nonserotonergic cells were retrogradely labeled after tracer injection into the MRN. It is then possible that not all of the retrogradely labeled fibers are serotonergic. The general impression would be that 5-HT axons connecting 5-HT nuclei are "diluted" within the dorsal and median raphe neuropil.

An important afferent area to the raphe, both in terms of selectivity and density, is the lateral habenula (Aghajanian and Wang, 1977; Wang and Aghajanian, 1977b). This habenular circuit appears to be comprised of both a monosynaptic GABAergic pathway (Wang and Aghajanian, 1977b; Stern et al., 1981; Park, 1987) and a polysynaptic pathway in which GABA, Substance P (Neckers et al., 1979; Nishikawa and Scatton, 1985), and excitatory amino acids serve as components (Kalen et al., 1985, 1989).

Noradrenergic fibers impinge directly onto the dendrites of 5-HT neurons (Baraban and Aghajanian, 1981), producing an excitatory input on the firing activity of 5-HT neurons (Baraban and Aghajanian, 1980). The lateral hypothalamus also gives rise to a monosynaptic excitatory input to the DRN (Aghajanian et al., 1987) although the transmitter is unknown. Multiple afferent fibers immunoreactive for different neuropeptides, such as -endorphin (Bloom et al., 1978), Substance P (Ljungdahl et al., 1978; Shults et al., 1984), neurotensin fibers (Uhl et al., 1979), CCK fibers (Vanderhaeghen et al., 1980), CLIP/adrenocorticotrophic hormone (ACTH) fibers (Romagnano and Joseph, 1983; Zheng et al., 1991; Léger et al., 1994), and VIP fibers (El Kafi et al., 1994), have also been described.

D. Efferent Pathways and Terminal Projection Areas

1. Efferent Pathways. The rostral 5-HT nuclei are the main source of 5-HT fibers projecting to telencephalon and diencephalon (Fuxe, 1965; Azmitia and Segal, 1978; Parent et al., 1981; Villar et al., 1987). Although the main contingent of fibers from these nuclei is ascending, they also innervate more sparely numerous brainstem structures (Vertes and Kocsis, 1994), the cerebellar cortex (Waterhouse et al., 1986; Zimny et al., 1988), and the spinal cord (Skagerberg and Björklund, 1985). In the nonhuman primate brain, two main ascending bundles have been described, a dorsal bundle (immediately ventral to the MLF), which receives fibers mainly from lateral wings and the ventromedial portion of the DRN, and a ventral bundle, which receives fibers from the midline DRN and MRN (Schofield and Everitt, 1981, Azmitia and Gannon, 1986). In the human fetus, two ascending axon bundles have also been observed, in the central gray, ventral to the fourth ventricle and the aqueduct ependyma, and between ventromedial and ventrolateral 5-HT groups (Nobin and Bjorklund, 1973). In the rat CNS, two major projection systems to the forebrain have also been described, a transtegmental system, which probably corresponds to the above-mentioned ventral bundle, courses through the midbrain forebrain bundle (MFB) and is the most prominent of the two systems described by Descarries in the rat brain, and a periventricular system, dorsally located along the longitudinal fasciculus of Schütz (Parent et al., 1981). In primates, unlike in rats, the dorsal component (dorsal raphe cortical tract) is much more developed than the MFB system, presumably due to an increase in fibers projecting to the cortex through the dorsal pathway. Moreover, the percentage of myelinated 5-HT fibers in rat MFB is 0.7% of the total immunoreactive 5-HT fibers, whereas it is as much as 25% in primate MFB (Azmitia and Gannon, 1983).

2. Terminal Projection Areas. Dorsal and median raphe nuclei each innervate specific terminal areas (Bobillier et al., 1975; Azmitia and Segal, 1978; Jacobs et al., 1978), and, in turn, each terminal projection area has its unique topographic representation within the respective nuclei. Labeling studies using wheat germ agglutinin, horseradish peroxidase, or fluorescent dyes have been used to unveil the midbrain raphe projection network. The more rostral portions of the midbrain raphe relate to the basal-ganglia-motor system and caudal areas are more related to the limbic system. Neurons projecting to the striatum occupy the caudal linear nucleus and a rostral portion of the DRN (Jacobs et al., 1978; Imai et al., 1986), whereas those projecting to substantia nigra (Imai et al., 1986) and the motor cortex (O'Hearn and Molliver, 1984; Waterhouse et al., 1986) reside within the rostral portions of the dorsal raphe (Imai et al., 1986). Hippocampus-projecting neurons are situated caudally in the DRN (caudal ventromedial portion and B₆), the MRN, and B₉ (Jacobs et al., 1978; Köhler and Steinbusch, 1982; Imai et al., 1986), similar to neurons projecting to the locus ceruleus (Imai et al., 1986) and to the entorhinal cortex (Köhler and Steinbusch, 1982). The raphe representation of the amygdala, on the other hand, bridges the "basal-ganglia-motor system" and the "limbic system representation" (Jacobs et al., 1978; Imai et al., 1986), possibly as a reflection of the functional diversity of amygdaloid nuclei. The consequence of this topographic arrangement is that the selective activation of a given functional group would simultaneously influence interconnected brain circuits. Neurons projecting to interrelated brain circuits, such as the sensorimotor cortex and cerebellar crus II, the visual cortex and cerebellar paraflocculus (Waterhouse et al., 1986), or to the substantia nigra and caudate-putamen (Imai et al., 1986), the entorhinal cortex and hippocampus (Köhler and Steinbusch, 1982), the trigeminal sensory complex and nucleus accumbens or amygdala (Li et al., 1993), arise from overlapping areas within the different nuclei. Moreover, in these regions, a single neuron may provide a common input to two different but functionally interrelated terminal areas. In the ventromedial portion of the DRN, the same neuron was found to project to at least three different forebrain structures related with the limbic system: septum, medial thalamus, and olfactory cortex (de Olmos and Heimer, 1980). Colateralization provides not only a means for producing concurrent influences on numerous functionally related circuits, but it is also a way of achieving extensive serotonergic innervation from a small number of raphe neurons.

	III. Physiological and Pharmacological Aspects of the 5-HT System

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Midbrain raphe 5-HT neurons exhibit a spontaneous, slow (1-5 spikes/s), regular discharge pattern (Aghajanian and Vandermaelen, 1982; Vandermaelen and Aghajanian, 1983). Intracellular recordings from dorsal raphe neurons reveal that 5-HT cells undergo repetitive cycles of interspike hyperpolarization and depolarization, spikes arising from depolarizing ramps rather than from excitatory postsynaptic potentials (Aghajanian and Vandermaelen, 1982; Vandermaelen and Aghajanian, 1983). The ionic basis for this electrical activity is summarized in Fig. 1.

View larger version (12K): [in this window] [in a new window]   Fig. 1.   Representative voltage tracings obtained from acutely isolated DRN neurons under current clamp (modified from Penington et al., 1991). A, spontaneous activity exhibited by the cell at resting membrane potential. Typical action potentials consist of an initiating ramp of depolarization, spike, shoulder upon repolarization, and an after-hyperpolarization. B, depolarization of a cell bathed with the Na+ channel blocker TTX. TTX abolished the fast component of the action potential and uncovered low- and high-threshold Ca2+ components of the action potential. Although T channels seem to be responsible for the low-threshold current, at least three different channel types (including N- and L-type) underlie the high-threshold current (Penington and Kelly, 1990; Penington et al., 1991). The after-hyperpolarization that follows, as in many other vertebrae and invertebrae neurons, is mediated by a Ca2+-activated K+ outward current (Vandermaelen and Aghajanian, 1982; Aghajanian, 1985; Aghajanian et al., 1987). This after-hyperpolarization is responsible for a long-lasting refractory period and the slow firing rate of 5-HT neurons. As Ca2+ that entered during the action potential is sequestered/extruded, the Ca2+-dependent K+ current and the after-hyperpolarization decrease. When the membrane potential reaches again the value for the low-threshold Ca2+ current (approximately 60 mV), a new spike will be triggered. As repolarization from membrane potentials below the resting potential takes place, a voltage-dependent outward K+ current that slows the rate of depolarization is simultaneously activated, the so-called IA current (Aghajanian, 1985).

In freely moving cats, regular stereotyped intrinsic activity of 5-HT neurons remains unchanged over exposure to a hot environment or administration of a pyrogen, increase in blood pressure, insulin-induced hypoglycemia, administration of painful stimuli, physical restraint, or exposure to powerful aversive stimuli (see Jacobs and Fornal, 1993). However, the basic pattern of activity is not constantly the same, and it has been shown to change dramatically during the sleep-wake-arousal cycle. Firing activity progressively slows down from an aroused state through quiet waking and slow wave sleep (SWS), to become almost silent during rapid eye movement (REM) sleep (for review, see McGinty and Harper, 1976; Jacobs and Fornal, 1993). The suppression of firing of 5-HT neuron during REM sleep correlates well with the production of muscle atonia secondary to inhibition of motoneurons controlling antigravity muscles (Trulson et al., 1981; Steinfels et al., 1983). More recently, a relationship between motor output and 5-HT neuron activity has been observed. During quiet wakefulness, when cats engage in various types of stereotyped oral-buccal activities such as chewing and biting, licking, or grooming with the tongue, approximately 25% of DRN and MRN increase their firing activity 2- to 5-fold (see Jacobs and Azmitia, 1992; Jacobs and Fornal, 1993). This increased neuronal activity precedes the onset of stereotyped motor behaviors and ends with its offset; it does not occur during purposive episodic movements, but some of the neurons may be activated by somatosensory and proprioceptive stimulations of the head and neck area. These data have given support to the current motor hypothesis of 5-HT function in which the primary role of the 5-HT system would be facilitation of motor output and concurrent inhibition of sensory information processing (Jacobs and Fornal, 1993).

The firing activity of midbrain 5-HT neurons is controlled by two main mechanisms, i.e., autoregulatory influences arising from 5-HT neurons themselves and heteroregulation by local neurons or afferents to the raphe nuclei.

1. Autoregulation of 5-HT Neuron Firing Activity. The firing rate of 5-HT neurons is decreased by 5-HT, and this effect is mediated by somatodendritic 5-HT_1A autoreceptors (Aghajanian et al., 1972; Vandermaelen et al., 1986; Blier and de Montigny, 1987). 5-HT and 5-HT_1A agonists inhibit 5-HT firing activity by inducing membrane hyperpolarization which is brought about by a 2-fold mechanism, i.e., by increasing conductance to potassium ions (Aghajanian and Lakoski, 1984; Yoshimura and Higashi, 1985) and by reducing a high-threshold Ca²⁺ current (Fig. 1; Penington and Kelly, 1990; Penington and Fox, 1994). In both cases, the response to 5-HT is G protein-mediated via a direct interaction between G proteins and the respective ion channel (Innis and Aghajanian, 1987; Penington et al., 1991; Penington et al., 1993; Penington and Fox, 1994).