Distribution In The

As with the other monoamines, the distribution of 5-HT-releasing neurons in the brain was first characterised in the 1960s using the Falck-Hillarp histochemical technique whereby 5-HT is converted to a compound that is fluorescent under ultra-violet light. This showed that the cell bodies of 5-HT neurons aggregate around the midline of the upper brainstem, forming distinct clusters (or nuclei) (Fig. 9.2). Since then, 5-HT neurons have been found in the noradrenergic locus coeruleus and the area postrema as well. Yet, despite this relatively restricted distribution of cell bodies, their processes project more or less throughout the whole neuraxis. For a detailed review of this topic, see Jacobs and Azmitia (1992) but an outline of key features is given here.

The clusters of 5-HT cell bodies (the so-called Raphe nuclei) were originally perceived as forming nine separate nuclei (designated B1-B9) but current nomenclature has reclassified these to some extent so that, currently the nuclei incorporate cell bodies from more than one of those described originally (Table 9.1). Despite these changes, all these nuclei are still regarded as forming two major groups.

The so-called 'inferior' group (B1-B4) projects mainly to brainstem nuclei, the head nuclei of some cranial nerves and the spinal cord. This means that these neurons are well placed for serving a key role in regulation of motor activity, autonomic function and nociception. In addition, there are numerous interconnections between the different

Neurotransmitters, Drugs and Brain Function. Edited by R. A. Webster ©2001 John Wiley & Sons Ltd

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Neuronal uptake inhibitors

Imipramine Citaiopram

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Neuronal uptake inhibitors

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MAO inhibitors

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Phenelzine Reversible, selective: Moelobemide (MAO-A, 'RIMA)

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5-HT2fl;iC receptor

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S-HTlA receptor

5-HT2fl;iC receptor

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Figure 9.1 The distribution of 5-HT neurons in the brain. The cell bodies are clustered in nuclei (B1-B7) in the pons/upper medullary regions of the brainstem. The rostral cluster ('superior group') project mainly to forebrain areas while the caudal ('inferior') group projects mainly to the medulla and spinal cord. Collectively, these neurons innervate most regions of the central nervous system

Neocortex Hippocampus Thalamus Cerebellum

Human Brain Anatomy Neocortex

Figure 9.2 The site of action of drugs that modify 5-HT transmission

Pituitary

Figure 9.2 The site of action of drugs that modify 5-HT transmission

5-HT nuclei, as well as connections with other monoaminergic nuclei in the brainstem which are also implicated in these physiological functions.

Neurons in the 'superior' group (B5-B9) project rostrally, generally ipsilaterally, in six fibre tracts. The most prominent of these is the median forebrain bundle which contains both myelinated and unmyelinated 5-HT fibres. These mainly innervate limbic and sensory areas of the forebrain. Although extensive branching of the neuronal processes results in a considerable overlap in the terminal axonal fields of the different nuclei, there is evidence for some topographical organisation of the areas to which different nuclei project (Fig. 9.3). For instance, whereas fibres emanating from the dorsal Raphe nucleus (DRN) are the major source of 5-HT terminals in the basal ganglia and cerebellum, neurons in the median Raphe nucleus (MRN) provide the major input to the hippocampus and septum.

There is also some evidence for morphological differences between DRN and MRN neurons which could impinge on their function. Thus, the terminals of neurons from the DRN are relatively fine, unmyelinated, branch extensively and seem to make no specialised synaptic contacts, suggesting en passant release of 5-HT (type I). In contrast,

Table 9.1 The main subdivisions of 5-HT nuclei in the brain

Superior Inferior

Table 9.1 The main subdivisions of 5-HT nuclei in the brain

Superior Inferior

B6 and B7 Dorsal Raphe nucleus

B1 and B4

Nucleus Raphe pallidus

B5 and B8 Median Raphe nucleus

B2

Nucleus Raphe obscurus

B8 Caudal linear nucleus

B3

Nucleus Raphe magnus

B9 Nucleus prosupralemniscus

B1 and B3

Neurons of the lateral

paragigantocellular nucleus and the

intermediate reticular nuclei

Cells in the area postrema

Median Raphe Dorsal Raphe Innervation
Figure 9.3 Brain regions to which neurons in the dorsal and median Raphe nuclei project. Some areas are innervated by neurons from both nuclei (e.g. hypothalamus) whereas others are innervated predominantly by either the MRN (e.g. the hippocampus) or the DRN (e.g. the amydgala)

those from the MRN are broader, often myelinated, with large varicosities, and they seem to form specialised synaptic contacts, suggesting targeted release of 5-HT (type II). The existence of co-transmitters, especially substance P, thyrotropin releasing hormone (TRH) and enkephalin, gives further options for functional specialisation of different neurons but, as yet, the distribution of these peptides within different nuclei has provided no specific clues as to how this might occur. In any case, species differences in the distribution of co-transmitters is a confounding factor.

In short, although the 5-HT system seems to have a rather non-specific influence on overall brain function, in terms of the brain areas to which these neurons project, there is clearly much to be learned about possible functional and spatial specialisations of neurons projecting from different nuclei.

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