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1295190625 The Role of Serotonin in Depression Essay

1295190625 The Role of Serotonin in Depression Essay

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Published by: scholify on Jan 16, 2011
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The role of 5-HT in depression
5-HT's role in the central nervous system is unquestionably a significantone. However with the brain only accounting for approximately 2% of the total 5-HT in the body, one can observe that the neurotransmitter is extremely importantin peripheral synaptic transmission. Indeed the chemical was first isolatedsimultaneously in the smooth muscle by Rapport, Green and Page at theCleveland Clinic and from the gut by a group of scientists in Italy. In the first caseit was seen to bring on a powerful vasoconstriction of the vessels while in the gutits effects were similar, with the compound being found in particular abundance inthe chromaffin cells. However 5-HT's structure had not yet been determined andas a result the fluid collected from the smooth muscle was termed serotonin whilein the gut it was initially named enteramine. Eventually Rapport was able to mapout 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 thecentral nervous system, 5-HT is primarily synthesised in the neurons of the nineraphe nuclei, which lie to either side of the midline of the brainstem. While thecaudal raphe nuclei project towards the spinal cord, where they are thought tohave 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 ingreatest abundance in the pineal gland, an organ found within the connectivetissue surrounding the dorsal surface of the thalamus. With more than fifty timesas much 5-HT as the brain, this gland contains all the enzymes needed not onlyfor the synthesis of 5-HT but also a few additional enzymes for its conversion intoother useful molecules.  Synthesis of 5-HT by the pineal gland is known to becontrolled through a number of parameters including noradrenaline released bythe 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 uptakeprocess, which is in a way non-selective to neutral amino acids. Thus tryptophanlevels 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, thefirst one being tryptophan hydroxylase (TPH), which catalyses the reaction of tryptophan to 5-hydroxy-tryptophan, the rate-determining step. Amino aciddecarboxylase then converts this 5-HTP to 5-HT. The expression of TPH isthought to be affected by ovarian hormones and some believe this is the crux tothe concepts of premenstrual stress syndrome and postpartum depression.Having been released by the pre-synaptic neuron, 5-HT will diffuse acrossthe synaptic cleft and bind to 5-HT receptors. These receptors exist in sevendifferent classes, with only 5-HT3 receptor not being ionotropic and the remainder being G protein coupled seven transmembrane receptors. Each one mediates adifferent signal transduction mechanism leading to different overall effects. Theentire 5-HT1 receptor family are coupled to Gi proteins, initiating a reduction of cAMP levels through inhibition of adenylate cyclase however 5-HT1A also causesopening of K+ channels and closing of Ca2+ channels when activated in additionto the adenylate cyclase effects. 5-HT2 receptors are coupled to Gq, activating theenzyme phospholipase C, while 5-HT4 receptors are linked to Gs proteins, thusincreasing the levels of cAMP via promotion of adenylate cyclase. Themechanism of 5-HT5 receptors is not yet known but it is believed to be linkedwith 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 interms of depression but have been nonetheless very useful. Agonists of 5-HT1Dreceptors such as sumatriptan is administered for migraines, 5-HT3 receptor agonists e.g. Ondansetron are used as antiemetic compounds and tegaserod, a 5-HT4 receptor agonist can be prescribed to treat gut disorders such as irritablebowel syndrome. The recreational drug LSD acts at most 5-HT receptorsespecially 5-HT2A but not at the 5-HT3 and 5-HT4 receptors. The drug causeshallucinations and the remarkable similarities between the physical manifestationsof an individual who has taken LSD and one who has schizophrenia have givenrise to a belief that serotonergic neurons are involved with this condition.In order for the neurotransmission to be terminated, 5-HT is primarily takenup through a reuptake transporter found on the pre-synaptic nerve terminal. Thisaspect of 5-HT pharmacology is easily the most targeted in terms of pharmaceuticals. By inhibiting this monoamine transporter protein, one maintainsan elevated level of 5-HT in the synaptic cleft, which provides relief to individualsexperiencing depression. SERT spans the plasma membrane twelve times and canbe found throughout the entire CNS. The protein is transcribed by a gene knownas solute carrier family 6 neurotransmitter transporter and can be found onchromosome 17. Indeed some studies have shown that patients, who have amutation 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 monoamineuptake system of 5-HT. Perhaps the most popular class of antidepressantsprescribed today are the selective serotonin reuptake inhibitors (SSRIs). These actspecifically at the 5-HT uptake protein, reducing its activity, and are administeredto
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 andsertraline. Despite their benefits, they can cause nausea, insomnia, anorexia andfluoxetine has been thought to increase aggression. SSRIs are seldomly given inconjunction with monoamine oxidase inhibitors, another type of antidepressantwhich 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 andhyperthermia. Serotonin syndrome can also, in some cases, be caused by the drugMDMA. This compound binds to the 5-HT uptake transporter and not onlydecreases the amount of 5-HT taken back up by the neuron but it can reverse theaction of the pump so that 5-HT's levels intracellularly are depleted as theneurotransmitter is forced into the synaptic cleft.There are also less selective reuptake inhibitor classes such as the serotonin-noradrenaline reuptake inhibitors (SNRIs) and the noradrenergic and specificserotonergic antidepressants (NASSAs). SNRIs such as venlafaxine are used totreat anxiety disorders, OCD, attention deficit hyperactivity disorder (ADHD) andchronic neuropathic pain while NASSAs such as mirtazapine are used for depression. NASSAs have very few side effects while SNRIs are contraindicatedin patients suffering from heart disease and hypertension because of their adrenergic effects.Another more traditional class of antidepressants are the TCAs. These drugs

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