The role of 5-HT in depression

5-HT's role in the central nervous system is unquestionably a significant one. However with the brain only accounting for approximately 2% of the total 5HT in the body, one can observe that the neurotransmitter is extremely important in peripheral synaptic transmission. Indeed the chemical was first isolated simultaneously in the smooth muscle by Rapport, Green and Page at the Cleveland Clinic and from the gut by a group of scientists in Italy. In the first case it was seen to bring on a powerful vasoconstriction of the vessels while in the gut its effects were similar, with the compound being found in particular abundance in the chromaffin cells. However 5-HT's structure had not yet been determined and as a result the fluid collected from the smooth muscle was termed serotonin while in the gut it was initially named enteramine. Eventually Rapport was able to map out the structure of the neurotransmitter and demonstrated it to be that of 5-HT. As well as in the neurons of the brain, 5-HT can be found in a plethora of aspects of the human anatomy including the GI tract and platelets. In terms of the central nervous system, 5-HT is primarily synthesised in the neurons of the nine raphe nuclei, which lie to either side of the midline of the brainstem. While the caudal raphe nuclei project towards the spinal cord, where they are thought to have a role in the modulation of pain-related sensory signals, the rostral nuclei, found in the pons and midbrain, innervate most of the brain. 5-HT is found in greatest abundance in the pineal gland, an organ found within the connective tissue surrounding the dorsal surface of the thalamus. With more than fifty times as much 5-HT as the brain, this gland contains all the enzymes needed not only for the synthesis of 5-HT but also a few additional enzymes for its conversion into other useful molecules. Synthesis of 5-HT by the pineal gland is known to be controlled through a number of parameters including noradrenaline released by the sympathetic nervous system.

Production of 5-HT begins with tryptophan, which is mainly obtained through the

diet. This large neutral amino acid travels into neurons through an active uptake process, which is in a way non-selective to neutral amino acids. Thus tryptophan levels are dependent both on diet and competition with other neutral amino acids. Two enzymes are involved in the conversion of tryptophan ultimately to 5-HT, the first one being tryptophan hydroxylase (TPH), which catalyses the reaction of tryptophan to 5-hydroxy-tryptophan, the rate-determining step. Amino acid decarboxylase then converts this 5-HTP to 5-HT. The expression of TPH is thought to be affected by ovarian hormones and some believe this is the crux to the concepts of premenstrual stress syndrome and postpartum depression. Having been released by the pre-synaptic neuron, 5-HT will diffuse across the synaptic cleft and bind to 5-HT receptors. These receptors exist in seven different classes, with only 5-HT3 receptor not being ionotropic and the remainder being G protein coupled seven transmembrane receptors. Each one mediates a different signal transduction mechanism leading to different overall effects. The entire 5-HT1 receptor family are coupled to Gi proteins, initiating a reduction of cAMP levels through inhibition of adenylate cyclase however 5-HT1A also causes opening of K+ channels and closing of Ca2+ channels when activated in addition to the adenylate cyclase effects. 5-HT2 receptors are coupled to Gq, activating the enzyme phospholipase C, while 5-HT4 receptors are linked to Gs proteins, thus increasing the levels of cAMP via promotion of adenylate cyclase. The mechanism of 5-HT5 receptors is not yet known but it is believed to be linked with Gi while 5-HT6 and 5-HT7 receptors are coupled to Gs. Clinical drugs, which manipulate the action of the receptors, has had very little significance in terms of depression but have been nonetheless very useful. Agonists of 5-HT1D receptors such as sumatriptan is administered for migraines, 5-HT3 receptor agonists e.g. Ondansetron are used as antiemetic compounds and tegaserod, a 5HT4 receptor agonist can be prescribed to treat gut disorders such as irritable bowel syndrome. The recreational drug LSD acts at most 5-HT receptors especially 5-HT2A but not at the 5-HT3 and 5-HT4 receptors. The drug causes hallucinations and the remarkable similarities between the physical manifestations of an individual who has taken LSD and one who has schizophrenia have given rise to a belief that serotonergic neurons are involved with this condition. In order for the neurotransmission to be terminated, 5-HT is primarily taken up through a reuptake transporter found on the pre-synaptic nerve terminal. This aspect of 5-HT pharmacology is easily the most targeted in terms of pharmaceuticals. By inhibiting this monoamine transporter protein, one maintains an elevated level of 5-HT in the synaptic cleft, which provides relief to individuals experiencing depression. SERT spans the plasma membrane twelve times and can be found throughout the entire CNS. The protein is transcribed by a gene known as solute carrier family 6 neurotransmitter transporter and can be found on chromosome 17. Indeed some studies have shown that patients, who have a mutation in this particular region of the DNA and therefore an ineffective SERT, have a higher likelihood of acquiring obsessive compulsive disorder (OCD). A multitude of drugs have been developed, which address the monoamine uptake system of 5-HT. Perhaps the most popular class of antidepressants prescribed today are the selective serotonin reuptake inhibitors (SSRIs). These act specifically at the 5-HT uptake protein, reducing its activity, and are administered to

individuals with moderate degrees of depression, people with anxiety disorders, panic attacks and those with OCD. These have an advantage over older antidepressants in that they are less harmful in overdoses and also they do not bear the anticholinergic side effects often associated with the tricyclic antidepressants (TCAs). They comprise fluoxetine, fluvoxamine, paroxetine, citralopram and sertraline. Despite their benefits, they can cause nausea, insomnia, anorexia and fluoxetine has been thought to increase aggression. SSRIs are seldomly given in conjunction with monoamine oxidase inhibitors, another type of antidepressant which acts by inhibiting the enzyme responsible for 5-HT degradation. Together they can cause a toxic level of 5-HT in the body, termed serotonin syndrome, manifesting in symptoms such as cardiovascular collapse, tremor and hyperthermia. Serotonin syndrome can also, in some cases, be caused by the drug MDMA. This compound binds to the 5-HT uptake transporter and not only decreases the amount of 5-HT taken back up by the neuron but it can reverse the action of the pump so that 5-HT's levels intracellularly are depleted as the neurotransmitter is forced into the synaptic cleft.

There are also less selective reuptake inhibitor classes such as the serotoninnoradrenaline reuptake inhibitors (SNRIs) and the noradrenergic and specific serotonergic antidepressants (NASSAs). SNRIs such as venlafaxine are used to treat anxiety disorders, OCD, attention deficit hyperactivity disorder (ADHD) and chronic neuropathic pain while NASSAs such as mirtazapine are used for depression. NASSAs have very few side effects while SNRIs are contraindicated in patients suffering from heart disease and hypertension because of their adrenergic effects. Another more traditional class of antidepressants are the TCAs. These drugs

have a structure, which resembles that of the phenothiazines. They act as competitors for the amine uptake transporter in the pre-synaptic nerve terminal, affecting the levels of both 5-HT and noradrenaline and to a lesser degree dopamine. However they do cause several side effects and this is thought to be a result of their binding to neurotransmitter receptors on the post-synaptic neuron. These include tachycardia, dry mouth, urinary retention, blurred vision and diziness. Along with these side effects, TCAs also have a relatively dangerous therapeutic index with only ten times the normal dose generating toxic effects and these factors make it an uncommonly prescribed method of depression except for those being severely hindered. 5-HT, once taken up inside the neuron is broken down by monoamine oxidase into 5-HIAA. This enzyme can be inhibited thus encouraging higher levels of 5-HT in the cytoplasm. This increases the rate of spontaneous leakage and sensitises the neuron in a way to sympathomimetic amines such as amphetamines. Found on the outer membrane of the mitochondria, it exists in two types, MAO-A and MAO-B and different MAOIs can be selective for each type or non-selective such as in phenelzine and iproniazid, which act irreversibly. Some MAOIs such as moclobemide do act reversibly. MAO-B has a minor role in terms of 5-HT and is inhibited by selegilin, a useful drug for Parkinson's patients. Recently selegilin has been infused into a transdermal patch so as to avoid the uncomfortable GI side effects of the drug. MAO-A has a greater affinity for 5-HT and is targeted usually by antidepressant MAOIs. MAOIs have a rapid effect, affecting 5-HT, adrenaline and dopamine concentrations in the neuron and being responsible for the inactivation of several endogenous and ingested amines. MAOIs also account for many side effects, the most common of which is hypotension. This is believed to result from accumulation of other amines such as dopamine and octopamine, which force noradrenaline from its storage vesicles hence decreasing the secretion of this neurotransmitter concerned with the sympathetic nervous system. MAOI's can also increase appetite, and cause tremors, insomnia, blurred vision and urinary retention. In rare cases, MAOIs when taken with foods contraining the amine tyramine, such as cheese, can cause a state of severely elevated blood pressure and tachycardia. The so-called cheese syndrome is thought to occur because of the displacement of noradrenaline from its storage vesicles. Although drugs, which manipulate the 5-HT pathway, are known to act as effective treatments for depression, the specific neurological mechanism behind this emotion is very poorly understood. Indeed the development of such drugs has very much been a result of empiricism rather than scientific knowledge and understanding. Undoubtedly, as the convoluted nature of the depressed mind is unfolded, more aspects of neurotransmission will be identified as potential regions of targeting for antidepressants.

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