Raphe nucleus

SERT, 5HTT (SLC6A4) 5HT = serotonin -1 CNS serotonergic neurons (emanate from raphe nuclei) platelets, smooth muscle, intestine ... 

DAT is predominantly expressed by dopaminergic brain neurons, NET by noradrenergic neurons in the central and peripheral nervous system, and SERT is restricted to the axons of serotonergic neurons, which originate in the raphe nuclei and innervate numerous higher brain regions therefore SERT is widely distributed in the brain. Outside the brain, 5HT transport can be measured on non-neuronal cells (e.g. platelets, lympho-blastoid cells and smooth muscle cells) most of the 5HT appearing in the circulation is taken up by platelets. 

The raphe nuclei are a cluster of nuclei found in the brainstem, where they are located in the medial portion of the formatio reticularis, the raphe. (The raphe is the junction of the left and right brainstem hemisphere, hence the name raphe=seam). Serotonergic nerve cells in the CNS originate from the raphe nuclei, i.e., their rostral portion, and because of their wide-ranging projections appear to supply serotonin (5HT) to the rest of the brain. 

Enterochromaffin cells are interspersed with mucosal cells mainly in the stomach and small intestine. In the blood, serotonin is present at high concentrations in platelets, which take up serotonin from the plasma by an active transport process. Serotonin is released on platelet activation. In the central nervous system, serotonin serves as a transmitter. The main serotonin-containing neurons are those clustered in form of the Raphe nuclei. Serotonin exerts its biological effects through the activation of specific receptors. Most of them are G-protein coupled receptors (GPCRs) and belong to the 5-HTr, 5-HT2-, 5-HT4-, 5-HTs-, 5-HT6-, 5-HT7-receptor subfamilies. The 5-HT3-receptor is a ligand-operated ion channel. 

Localization CNS Hippocampus (CA1, CA3, DG), septum, amygdala, raphe nuclei CNS Striatum, hippocampus (CA1), substantia nigra, globus pallidus, superior colliculi, spinal cord, raphe nuclei CNS like 5-HT1B but at lower densities. CNS Caudate putamen, parietal cortex, fronto-parietal motor cortex, olfactory tubercle, amygdala CNS Cortex, Thalamus, olfactory bulb (rat), claustrum (g-pig), hippocampus (CA3), spinal cord. 

Localisation CA/S Hippocampus (CA1, CA3, DG), cortex, cerebellum (granular layer), olfactory bulb, habenula, spinal cord CA/S Caudate putamen, olfactory tubercle, nucleus accumbens, cortex, hippocampus (CA1, CA3, DG) CA/S Hippocampus (CA1, CA2), hypothalamus, thalamus, superior colliculus, raphe nuclei... 

ACh is widely distributed throughout the brain and parts of the spinal cord (ventral horn and dorsal columns). Whole brain concentrations of lOnmolg" tissue have been reported with highest concentrations in the interpeduncular, caudate and dorsal raphe nuclei. Turnover figures of 0.15-2.0 nmol g min vary with the area studied and the method of measurement, e.g. synthesis of labelled ACh from [ " C]-choline uptake or rundown of ACh after inhibition of choline uptake by hemicholinium. They are all sufficiently high, however, to suggest that in the absence of synthesis depletion could occur within minutes. 

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)...

The apparent reliance of enzyme activation on phosphorylation and intracellular Ca + gives a clue as to how the rate of 5-HT synthesis might be coupled to its impulse-evoked release. Certainly, the impulse-induced increase in intracellular Ca +, and/or activation of the G protein-coupled receptors that govern synthesis of cAMP, could modify the activity of tryptophan hydroxylase. Indeed, this could explain why activation of either somal 5-HTia autoreceptors in the Raphe nuclei (which depress the firing rate of 5-HT neurons) or terminal 5-HTib autoreceptors (which depress 5-HT release) can reduce the production of cAMP and attenuate 5-HT synthesis. 

Impulse-evoked release of 5-HT, like that of noradrenaline, is subject to fine control by a system of autoreceptors, in particular 5-HTia receptors on the cell bodies of neurons in the Raphe nuclei and 5-HTib/id receptors on their terminals. Because these are all G /o protein-coupled receptors, their activation reduces the synthesis of cAMP so that 5-HTia agonists (or 5-HT itself) decrease neuronal excitability and the firing of Raphe neurons whereas activation of 5-HTib/id receptors seems to disrupt the molecular cascade that links the receptor with transmitter release (see Chapter 4). 

As might be expected, mRNA for the 5-HT transporter is found in high concentrations in the Raphe nuclei but it is also found in other brain regions. Whether this means that non-5-HT neurons can synthesise this protein is unknown but there is some evidence that it is synthesised in astrocytes, at least. One complication is that there are multiple forms of mRNA for the 5-HT transporter, but there is, as yet, no evidence for transporter subtypes in the CNS. However, it must also be remembered that 5-HT transporters are found in the peripheral tissues, notably platelets, mast cells, the placental brush-border and adrenal chromaffin cells and it is possible that these are not all identical. 

Although the distribution of these receptors is widespread in the brain, they are found postsynaptically in high concentrations in the hippocampus, septum and amygdala and also on cell bodies of 5-HT neurons in the Raphe nuclei. They are negatively coupled, via Gj/o/z proteins, to adenylyl cyclase such that their activation reduces production of cAMP. In turn, this leads to an increase in K+ conductance and hyperpolarisation of... 

So far, little is known about this novel 5-HTid receptor but, in the rat and human, its mRNA is found, albeit in low concentrations, in the basal ganglia, nucleus accumbens, hippocampus, frontal cortex and Raphe nuclei. It is negatively coupled to adenylyl cyclase and is possibly located presynaptically, on both the 5-HT neuronal cell body and terminals, but this has yet to be confirmed. 

Overall, it remains to be seen whether or not changes in the release of 5-HT in the terminal field parallel changes in the firing rate of neurons in the Raphe nuclei. Certainly the network of hetero- and presynaptic receptors, described above, could make it feasible to adjust 5-HT release in the terminal field despite the clock-like firing... 

Adell, A, Casanovas, JM and Artigas, F (1997) Comparative study in the rat of the actions of different types of stress in the release of 5-HT in the raphe nuclei and forebrain areas. 

Dourish, CT, Hutson, PH and Curzon, G (1986) Putative anxiolytics 8-OHDPAT buspirone and TVXQ 7821 are agonists at 5-HTia autoreceptors in the raphe nuclei. Trends Pharmacol. Sci. 1 212-214. 

Figure 20.6 Schematic representation of the effects of 5-HT reuptake inhibitors on serotonergic neurons, (a) 5-HT is released at the somatodendritic level and by proximal segments of serotonergic axons within the Raphe nuclei and taken up by the 5-HT transporter. In these conditions there is little tonic activation of somatodendritic 5-HTia autoreceptors. At nerve terminals 5-HTib receptors control the 5-HT synthesis and release in a local manner, (b) The blockade of the 5-HT transporter at the level of the Raphe nuclei elevates the concentration of extraneuronal 5-HT to an extent that activates somatodendritic autoreceptors (5-HTia). This leads to neuronal hyperpolarisation, reduction of the discharge rate and reduction of 5-HT release by forebrain terminals, (c) The exposure to an enhanced extracellular 5-HT concentration produced by continuous treatment with SSRIs desensitises Raphe 5-HTia autoreceptors. The reduced 5-HTia function enables serotonergic neurons to recover cell firing and terminal release. Under these conditions, the SSRI-induced blockade of the 5-HT transporter in forebrain nerve terminals results in extracellular 5-HT increases larger than those observed after a single treatment with SSRIs. (Figure and legend taken from Hervas et al. 1999 with permission)...

There are other important sites of opiate actions located in the 5-HT and noradrenergic nuclei of the brainstem and midbrain including the raphe nuclei, the periaquaductal... 

Figure 22.1 Pathways projecting to and from the suprachiasmatic nucleus (SCN). Inputs from photoreceptors in the retina help to reset the circadian clock in response to changes in the light cycle. Other inputs derive from the lateral geniculate complex and the serotonergic, Raphe nuclei and help to reset the SCN in response to non-photic stimuli. Neurons in the SCN project to the hypothalamus, which has a key role in the regulation of the reproductive cycle, mood and the sleep-waking cycle. These neurons also project to the pineal gland which shows rhythmic changes in the rate of synthesis and release of the hormone, melatonin...

Figure 22.8 The distribution of brainstem Raphe nuclei. Neurons that release 5-HT are clustered in two groups of nuclei in the pons and upper brainstem. The superior group, which projects to forebrain areas, includes the dorsal Raphe nucleus (DRN) and the median Raphe nucleus (MRN). The inferior group projects to the medulla and spinal cord and includes the nucleus Raphe pallidus (NRP), the nucleus Raphe obscurus (NRO) and the nucleus Raphe magnus (NRM)...

Fuxe 1965) and throughout the brain stem and spinal cord. A series of studies employing small intracerebral lesions (Anden et al. 1966 Ungerstedt 1971) indicated that most 5-HT nerve terminals in the forebrain arise from raphe nuclei in the midbrain and that the axons ascend through the lateral hypothalamus within the medial forebrain bundle (Moore and Heller 1967 Azmitia 1978 Conrad et al. 1974). 

Azmitia, E.C. The serotonin-producing neurons of the midbrain median and dorsal raphe nuclei. In Iversen, L.L. Iversen, S.D. and Snyder, S.H.. eds. Handbook of Psychopharmacology. Vol. 9. New York Plenum Press, 1978. pp. 233-314. 

Azmitia, E.C., and Segal, M. An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J Comp Neurol 179 641-668, 1978. 

Conrad, L.C.A. Leonard, C.M. and ffaff, D.W. Connections of the median and dorsal raphe nuclei in the rat Autoradiographic and degeneration study. J Comp Neurol 156 179-206. 1974. 

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