Neuroanatomy Of The Serotonin System

Only 2% of the serotonin (5-hydroxytryptamine [5-HT]) in the body is found in the brain. The neurons within the brain synthesize 5-HT, starting with the amino acid tryptophan, which is then hydroxylated via the enzyme tryptophan hydroxylase to form 5-hydroxytryptophan. 5-HT is then formed by decarboxylation of 5-hydroxytryptophan. Similar to DA, reuptake via the serotonin transporter (SERT) is the principal mechanism for terminating serotonergic neurotransmission. SERT also regulates the availability—and hence the signaling potential—of released 5-HT. Consequently, the strength of 5-HT activity at 5-HT receptors is inversely proportional to the number of functional SERT molecules present at the presynaptic membrane. Selective serotonin reuptake inhibitors (SSRIs) and related antidepressant drugs exploit this relationship by blocking the reuptake of 5-HT by SERT, thus increasing the levels of

5-HT in the synaptic cleft. In humans, the gene encoding for SERT exists in both long and short forms, with the short form resulting in lower levels of SERT expression. Azmitia and Gannon (1986) have provided a detailed description of the primate 5-HT system.

Cell Locations

The highest concentration of 5-HT-containing neurons in the mammalian brain is found in the raphe nuclei of the brain stem (see Figure 4-1). The cellular morphology and anatomical distribution of 5-HT neurons indicate that the raphe nuclei can be divided into rostral and caudal brain stem groups in the monkey and human brain stem (Hornung 2003). The principal subdivisions of the rostral raphe nuclei consist of the median raphe, dorsal raphe, and caudal linear nuclei located in the pons and midbrain. The caudal raphe nuclei consist of the raphe pallidus, raphe obscurus, and raphe magnus located in the caudal pons and medulla. The rostral raphe nuclei provide the bulk of the ascending axonal projections to the cerebral cortex and other subcortical structures, whereas the caudal raphe nuclei give rise to descending projections to the lower brain stem and spinal cord (Hornung 2003). Because of the functional and clinical importance of the 5-HT input to the cerebral cortex and limbic forebrain provided by the rostral nuclei, the following anatomical description of the 5-HT system will focus on the rostral raphe nuclei and their axonal projections.

The most rostral 5-HT neurons are located in the interpeduncular nucleus of the ventral mesencephalon (Hornung 2003). The caudal linear nucleus, located dorsal and caudal to the interpeduncular nucleus, lies between the red nuclei and contains both 5-HT and DA neurons. The most diverse of the raphe nuclei is the dorsal raphe nucleus (Baker et al. 1990). It is located in the central gray matter ventral to the cerebral aqueduct and fourth ventricle. On the basis of the topography and density of neurons in the primate, the dorsal raphe can be subdivided into five distinct subnuclei. Of these subnuclei, the ventrolateral subnucleus exhibits the highest density of 5-HT neurons in the entire brain stem (Baker et al. 1990). Postmortem studies have revealed abnormalities such as increased mRNA and protein levels of tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of 5-HT, in the dorsal raphe nucleus of suicide victims (Bach-Mizrachi et al. 2006). The median raphe extends from the caudal midbrain into the rostral pons (Tork and Hornung 1990). Serotonin neurons in the rostral level of the median raphe are densely packed along the midline, whereas at caudal levels, the nucleus expands laterally to form its characteristic barrel-shaped appearance. The barrel-like appearance is formed by the development of the paramedian raphe nuclei, which straddle the midline and contain both 5-HT neurons and 5-HT axons that arise from more caudal levels.

Projection Sites

The cerebral cortex is a major recipient of 5-HT axons arising from the mesencephalon. The heaviest projections to the frontal cortex, including prefrontal (see Figure 4-3) and motor cortices, arise from the dorsal raphe (M. A. Wilson and Molliver 1991). The median raphe and supralemniscal group project equally to the parietal, occipital, and frontal cortices. Unlike DA axons in the DA system, 5-HT axons are homogeneously distributed across different cortical areas, with the greatest density of axons usually present in the middle cortical layers (Morrison and Foote 1986). Furthermore, within cortical areas such as the prefrontal cortex, the density of 5-HT axons across regions is homogeneous (see Figure 4-4).

Although this area has been less well studied in primates, investigations in rodents suggest that the median raphe and dorsal raphe projections to the cerebral cortex are distinct in a number of respects (Mamounas and Molliver 1991). The cortical 5-HT axons originating from the median raphe are characterized by the presence of large spherical varicosities with thin intervaricose segments that give these axons a beaded appearance. In contrast, cortical axons originating from the dorsal raphe are fine and tortuous, with irregularly spaced small varicosities. Most cortical regions contain both types of 5-HT axons; however, the intracortical distribution of 5-HT axons is not uniform. For example, in the primate prefrontal cortex, the fine axons are present in all layers but are more abundant in layers 3-6, whereas the beaded axons predominate in layers 1-2 (Smiley and Goldman-Rakic 1996). These distinct morphological features of 5-HT axons, together with the unique topographical distributions, suggest that different functional roles for the two 5-HT fiber systems may exist. For example, in both rodents and primates, administration of amphetamine derivatives, such as methylenedioxyamphetamine and p-chloroamphetamine, causes selective degeneration of fine 5-HT-containing axons, whereas the beaded axons are spared (Mamounas and Molliver 1991; Molliver et al. 1990).

Interestingly, the effects of SSRIs differ based on the brain region and cellular localization of SERT. For example, blocking SERT in 5-HT projection fields (e.g., in the cerebral cortex) increases 5-HT levels and signaling at all available 5-HT receptors. By contrast, blocking SERT at the 5-HT cell body level (e.g., in the raphe nuclei) leads to increased activation of 5-HT1 autoreceptors (see subsection below titled "Receptors"), ultimately resulting in reduction of overall 5-HT function. Eventually, 5-HT output is increased through desensitization of 5-HT1 autoreceptors by SSRIs.

With regard to 5-HT synapses in primate cortex, the presence of 5-HT-labeled varicosities does not necessarily correspond to 5-HT synaptic specializations. In fact, it has been reported that more than three-quarters of 5-HT varicosities in the primate cortex do not form identifiable synaptic specializations, even though many had synaptic vesicles and accumulated 5-HT immunoreactivity (Smiley and Goldman-Rakic 1996). These observations suggest that 5-HT release, like that of DA, may occur at sites other than identified synapses and support the concept that nonsynaptic mechanisms of 5-HT neurotransmission are present in the primate cortex.

The raphe nuclei also project to a number of subcortical structures. The rostral group, including the caudal linear and dorsal raphe nuclei, project to the caudate, putamen, substantia nigra, and thalamus. In the primate, the 5-HT innervation of the thalamus is heterogeneous and widespread. The midline, rostral intralaminar, and reticular nuclei are the most densely innervated, whereas the ventral anterior and habenula are sparsely innervated (Lavoie and Parent 1991). The median raphe and the interfascicular subnucleus of the dorsal raphe project to limbic structures such as the hippocampus, amygdala, and septum. Serotonin neurons in both the median raphe and dorsal raphe contain highly collocated axons that innervate multiple terminal fields. This axonal organization pattern suggests that functionally related nuclei can be innervated by the same group of 5-HT neurons or even the same individual neuron.


Physiological and biochemical studies have revealed that multiple receptors exist for 5-HT and that many of these receptors have subtypes. To date, 14 5-HT receptors have been identified. The current classification of 5-HT receptors is based on structural characteristics and the second-messenger systems that are utilized. All but one of the 5-HT receptors belong to the G protein receptor superfamily. The exception is the 5-HT3 receptor, which belongs to the ligand-gated ion channel family (Peroutka 1997).

As with the other monoamine systems, the distribution of 5-HT receptors has been studied mostly in rodents by localization of receptor mRNAs. However, studies conducted in human subjects reveal receptor mRNA distributions similar to those in rodents. The 5-HT1 receptor has six subtypes, 5-HTj.a-f (Peroutka 1997). Several of the 5-HT1 subtypes—5-HTj.A, 5-HTj.b, and 5-HTj.o—appear to also function presynaptically, because the mRNA for these subtypes has been localized to 5-HT-containing neurons in both the dorsal and median raphe. Thus, these receptors also function as autoreceptors, regulating the firing of raphe neurons. In addition, 5-HTj.a and 5-HTj.b receptors, as revealed by immunocytochemistry and autoradiography, are present in the cerebral cortex as well as other projection sites of the dorsal raphe and median raphe (DeFelipe et al. 2001; Goldman-Rakic et al. 1990; Jakab and Goldman-Rakic 2000; Mengod et al. 1996).

The 5-HT2 receptor has three subtypes, 5-HT2a-c (Peroutka 1997). The most widely studied of these is the 5-HT2A subtype, the mRNA of which is most abundant in the cerebral cortex. In most cortical areas, layers 1 and 3-4 have a higher density of 5-HT2A mRNA levels than layers 2 and 5-6 (Lopez-Gimenez et al. 2001b). In monkey prefrontal cortex, the 5-HT2A receptor appears to be expressed by pyramidal cells as well as in the parvalbumin-containing subclass of nonpyramidal neurons (Jakab and Goldman-Rakic 2000), which provide potent inhibitory input to pyramidal cells. Subcortical structures, including the caudate, putamen, substantia nigra, and inferior olive, also express 5-HT2A mRNA (Lopez-Gimenez et al. 2001b). The anatomical localization of the 5-HT2B receptor has not been extensively studied, but the cerebral cortex has been shown to contain the mRNA for this receptor (Mengod et al. 1996). The 5-HT2B receptor mRNA is also localized to the cerebral cortex, whereas the 5-HT2C receptor mRNA has been identified in the hypothalamus and medulla (Mengod et al. 1996). The mRNA for the 5-HT2C receptor has been localized to layer 5 of cerebral cortex, nucleus accumbens, caudate, putamen, septal nuclei, diagonal band, ventral striatum, and extended amygdala (Lopez-Gimenez et al. 2001a). Increased binding of both 5-HT1A and 5-HT2A receptors has been found in the prefrontal cortex of suicide victims (Mann et al. 1986), possibly representing an upregulation of receptors due to decreased serotonergic transmission.

The 5-HT3 receptor mRNA has been identified in rodent cerebral cortex, where it was found to be collocated with GABA-containing neurons (Tecott et al. 1993). In addition, in monkey prefrontal cortex, the 5-HT3 receptor has been localized to small GABA-containing neurons that also express substance P and the calcium-binding protein calbindin (Jakab and Goldman-Rakic 2000).

The anatomical distribution of the 5-HT4 receptor has been examined by autoradiography in human brain, and areas with the highest levels of receptors are in the basal ganglia nuclei (caudate, putamen, nucleus accumbens, globus pallidus, and substantia nigra) and the hippocampus, specifically area CA1 and subiculum (Varnas et al. 2003). In neocortex, the superficial layers have higher levels of 5-HT4 receptor than the deeper cortical layers.

In rodent brain, the 5-HT7 receptor protein is found in the cerebral cortex, hippocampus, thalamus, and hypothalamus, with a somatodendritic localization in these areas (Neumaier et al. 2001). In human brain, 5-HT7 receptors, visualized via autoradiography, are also found in the cerebral cortex, hippocampus, and thalamus, as well as in the caudate and putamen (Martin-Cora and Pazos 2004).

The anatomical localization of the remaining 5-HT receptors (i.e., 5-HTsa-b, 5-HT6) has not been as well studied. However, mRNA for these receptor subtypes appears to be predominantly localized to subcortical structures, such as the caudate, nucleus accumbens, hippocampus, thalamus, and amygdala.

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