Serotonin owes its name to its discovery in serum, as a compound that makes muscles contract. Serotonin is also present in blood platelets, chromaffin cells of the intestinal mucosa and in the central nervous system.
Serotonin is synthesised (see Figure 6) from the essential amino acid tryptophan. Tryptophan is converted to 5-hydroxytryptophan by the enzyme tryptophan-5-hydroxylase, that is converted by l-aromatic amino acid decarboxylase to form serotonin. The synthesis is limited by the availability of tryptophan.
Figure 6. The synthesis and metabolism of serotonin.
NH2 N H COOH tryptophan tryptophan-5-hydroxylase NH 2 N H O H COOH 5-hydroxytryptophan
L-aromatic amino acid decarboxylase
N H O H COOH 5-hydroxyindoleacetic acid (5-HIAA) N H O H NH2 5-hydroxytryptamine (serotonin, 5-HT) monoamine oxidase aldehyde dehydrogenase
After release of 5-HT, its action is terminated by the reuptake of serotonin through 5-HT transporters in the presynaptic membrane. Serotonin is also metabolised by monoamine oxidase and aldehyde dehydrogenase to yield 5-hydroxyindole-3-acetic acid (5-HIAA). When serotonin is released in the synaptic cleft after an action potential, it exerts its effects via a multitude of 5-HT receptors. So far 7 families of receptors are known (5-HT1-7) with 15
subtypes. All of these receptors are G-protein coupled, except the 5-HT3 receptor that is an
ion-channel receptor.
Figure 7. Schematic representation of a serotonergic neurone with pre- and postsynaptic serotonergic receptors.
The 5-HT1A receptor exists both as postsynaptic receptor (in the hippocampus, septum, cortex,
amygdala and other limbic structures) and as a presynaptic receptor that occurs on the cell body (mainly in the raphe nuclei). The postsynaptic receptor is a heteroreceptor, and can also be found on neurones that use other neurotransmitters, like NA. The presence of such heteroreceptors means that an alteration in serotonergic neurotransmission may modulate non-serotonergic systems as well. As presynaptic receptor it suppresses the activity of the serotonergic neurons.
Also 5-HT1B/D receptors are found presynaptically, on axon terminals, where they inhibit the
release of more 5-HT [71]. The highest density is found in the substantia nigra, but also in the hippocampus, caudate and the putamen. The 5-HT1B receptor can also exist on non-
serotonergic neurons, and there may modulate the release of NA, dopamine, glutamate and GABA. Not only does 5-HT influence its own release, but GABA and histamine also have inhibitory effects on serotonergic neurotransmission [145]. Conversely, noradrenaline and glutamate have an excitatory influence [145].
5-HT2 receptors are found postsynaptically, as are 5-HT3 receptors [145, 153].
The cell bodies of serotonergic neurons form clusters. The five caudally located clusters project to the spinal cord, whereas the four most rostral clusters in the dorsal and median raphe nuclei (DRN and MRN) project to the mid- and forebrain [145]. The effect of serotonin in the brainstem and spinal cord is mostly that of excitation, whereas it is usually inhibitory in the forebrain [145].
Figure 8. Serotonergic pathways in the rodent brain. Adapted from [48].
As can be taken from Figure 8, the serotonergic pathways project to a multitude of brain regions, that are involved in a host of functions. Serotonin is therefore involved in sleep and arousal, feeding behaviour, sexual behaviour, pain perception, the control of body temperature, memory formation, the regulation of mood and of motor behaviour, to name a few [48, 145, 189, 280]. The neurons originating from the dorsal and the median raphe nucleus project to different brain structures but with considerable overlap. Limbic structures seem to be mainly innervated from the median raphe nucleus, whereas structures in the basal ganglia, like the striatum, are primarily innervated from the dorsal raphe nucleus [258]. Inputs to the raphe nuclei arise from brainstem nuclei such as the ventral tegmental area (via dopaminergic neurons) and the locus coeruleus (LC, via noradrenergic neurons). Interestingly, the prefrontal cortex, hyperactive in some anxiety and depressive states, can inhibit raphe activity via 5-HT1A- and GABAA receptors [50, 87, 173], although, after depletion of 5-HT,
activation of the mPFC resulted in activation of the raphe nuclei, mediated by glutamate receptors [50].
7.1.2. Involvement in stress, anxiety and depression
Reciprocal interactions between the serotonergic system and the HPA axis have been described. Neurons from the raphe nuclei project to the PVN, where 5-HT influences the levels of CRH, ACTH and other stress hormones through 5-HT1A and 5-HT2A receptors [57,
124, 238, 327]. Most information from the raphe nuclei however reaches the PVN via GABA-ergic interneurons. 5-HT thus probably influences the PVN indirect via heavy innervation of limbic structures [237]. 5-HT also modulates the negative-feedback of glucocorticoids on the HPA axis [141, 194, 285].
Conversely, stress is associated with increased activity of the dorsal and median raphe nuclei [54, 129, 185, 250, 318], and most researchers find increases in the extracellular levels of 5- HT or in the activity of serotonergic neurons in several brain areas under stressful conditions (reviews: [54, 193, 277]). The 5-HT synthesis rate is reduced in adrenalectomised animals [331], which effect is probably mediated over GR receptors in the hippocampus that are projecting to the raphe nuclei. In the hippocampus, MR and GR are often colocalised with the 5-HT1A receptor, the expression of which is suppressed by corticosterone [146]. The
expression of the 5-HT1A receptor can be influenced by corticosterone [52].
Serotonin, the serotonin transporter and practically all receptor subtypes also play a role in anxiety and depression [193, 207]. Indications for this are that the chance of a depression increases if one interferes with the availability of tryptophan, or when the synthesis of serotonin is blocked by PCPA (parachlorophenylalanine). Suicide victims also show reduced levels of serotonergic markers [78, 192].
A reduction in the serotonin transporter availability was found in the brains of depressed patients [196] and of patients with a generalised anxiety disorder [143]. Also the allele for the short form of the serotonin transporter promoter is associated with a poor response to SSRI [225].
Knockout mouse models of the 5-HT1A receptor induced an increase in anxiety like behaviour
[133, 241]. The selective 5-HT1A agonist buspirone is effective in the treatment of anxiety
and depression [331]. A 5-HT1B knockout had a less anxious behavioural profile [201, 353].
5-HT2A receptor antagonists decreases the behavioural and physiological responses to stress,
antagonists appear to be anxiolytic, but the latter unfortunately have an increased food-intake and weight gain as a side effect.
Chronic treatment with antidepressants cause levels of 5-HT in the forebrain structures and in the raphe nuclei to increase [18, 33], along with a reduction in the density of 5-HT2 receptors
[274] and an increase in the density of 5-HT1A receptors [75, 131].
In preclinical models of anxiety an increase of 5-HT function is associated with aversive behaviours. Conversely, drugs that reduce serotonergic function reverse fearful behaviours. Acute administration of SSRIs increase serotonergic concentrations by blocking the serotonin reuptake transporter. Indeed, the acute administration of SSRIs is known to first increase anxiety symptoms in patients. This elevation in 5-HT however is tempered by activation of autoreceptors that inhibit further release of 5-HT. With time, the autoreceptors become less responsive. Simultaneously, postsynaptic 5-HT receptors become downregulated, and also other systems may be influenced, resulting in the antidepressant and anxiolytic properties of SSRI [153].
7.2. Noradrenaline