Presentator : Dr. T.RavikanthModerators: Dr. Sharbandh Raj Dr. Swaroopa Chary
Introduction Synthesis. Degradation. Serotonin Receptors. Pathways in Brain. Disorders associated with malfunctioned Serotonergic System. Drugs affecting on serotonergic System
Introduction Serotonin is a monoamine neurotransmitter. extensively in GIT 80 to 90 percent - enterochromaffin cells in the gut, where it is used to regulate intestinal movements. The remainder is synthesized in serotonergic neurons in the central nervous system. Despite the abundance of peripheral serotonin, its inability to cross the BBB necessitates the synthesis of serotonin within the brain. Serotonin is synthesized from the amino acid tryptophan, which is derived from the diet.
Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.
Majority released from gut Responsible for smooth muscle contractions Release stimulated by food intake Inhibits release of gastric acid Softens stool Cardiovascular system – vasoconstrictor Bronchioconstriction Uterine contractions
Peripheral Peristalsis Vomiting Platelet aggregation and haemostasis Inflammatory mediator Sensitisation of nociceptors
Central Control of appetite Sleep Mood Hallucinations Stereotyped behaviour Pain perception Vomiting
(Rate OH COOH limiting) COOH Tryptophan C NH2 hydroxylase C NH2 N N In diet. Active Tryptophan CNS transport 5-Hydroxytryptophan 5-OH Tryptophan decarboxylase C COOH OH H N C NH25-Hydroxy Indole N Acetic Acid 5-OH Indole Acetaldehyde 5-Hydroxytryptamine
14 distinct serotonin receptor subtypes The 5-HT1 receptors = largest subfamily The most intensively studied of these has been the 5-HT1A receptor. This subtype is found on both postsynaptic membranes of forebrain neurons primarily in the hippocampus, cortex, and septum and on serotonergic neurons. It also functions as a somatodendritic autoreceptor.
•5-HT1 receptors occur primarily in the brain and cerebralblood vessels (5-HT1D only), where they mediate neuralinhibition and vasoconstriction.•They function mainly as inhibitory presynaptic receptors,linked to inhibition of adenylate cyclase.•Specific agonists at 5-HT1 receptors include •Sumatriptan (used in migraine therapy) •Buspirone (used in the treatment of anxiety).•Spiperone and methiothepin are specific antagonists of 5-HT1 receptors.
5–HT2 7 trans–membrane domains G protein linked Phospholipase C dependant Subtypes 5–HT2A, 5–HT2B, 5–HT2C
5–HT2A Periphery Contraction of vascular /non–vascular smooth muscle Platelet aggregation Increased capillary permeability Cognitive process of working memory, a function believed to be impaired in schizophrenia. Modulation of the release of other neurotransmitters and hormones ACh, Adrenaline, Dopamine, Excitatory amino acids, Vasopressin
•5-HT3 receptors occurmainly in the peripheralnervous system,particularly on nociceptiveafferent neurones and onautonomic and entericneurones.•The effects of thesereceptors are excitatory,mediated by receptor-coupled ion channels.•5-HT3 antagonists (egondansetron, tropisetron)are used predominantly asanti-emetic drugs.
5-HT4 receptors are found in the brain, as well as peripheral organs like the heart, bladder and gastrointestinal (GI) tract. stimulating peristalsis. A specific 5-HT4 agonist is metoclopramide used for treating gastrointestinal disorders. Little is known about the function and pharmacology of 5-HT5, 5-HT6 and 5-HT7 receptors.
Serotonin has both ascending & decending projections. Ascending serononergic projections Serotonergic neurons are clustered in midline raphe nuclei of the midbrain, pons, and medulla Ascending projections from these nuclei course through the medial forebrain bundle before diverging to many target regions. median raphe nucleus provides the majority of the serotonergic innervation of the limbic system, including the hippocampus and septum, dorsal raphe nucleus provides the primary innervation of the striatum and thalamus.
Decendng serononergic projection extend down the brainstem, and through the spinal cord. The caudal raphe serotonergic neurons project to the medulla, cerebellum, and spinal cord. Serotonergic efferents to the dorsal horn of the spinal cord have been implicated in the suppression of nociceptive pathways.
1. Mood Disorders2. Anxiety Disorder3. Schizophrenia4. ADHD5. Sexual Disorders6. Impulse Control Disorder7. Personality disorders8. Carcinoid syndrome
With the huge effect that the selective serotonin reuptake inhibitors (SSRIs) for example, fluoxetine have made on the treatment of depression, serotonin has become the biogenic amine neurotransmitter most commonly associated with depression. The identification of multiple serotonin receptor subtypes has also increased the excitement within the research community about the development of even more specific treatments for depression. Depletion of serotonin may precipitate depression, and some patients with suicidal impulses have low cerebrospinal fluid (CSF) concentrations of serotonin metabolites and low concentrations of serotonin uptake sites on platelets.
Different types of acute stress result in increased 5-HT turnover in the prefrontal cortex, nucleus accumbens, amygdala, and lateral hypothalamus. 5-HT release may have anxiogenic and anxiolytic effects, depending on the region of the forebrain involved and the receptor subtype activated. Anxiogenic effects are mediated via 5-HT2A receptor, stimulation of 5-HT1A receptors is anxiolytic. serotonergic antidepressants have therapeutic effects in some anxiety disorders for example, clomipramine (Anafranil) in OCD. The effectiveness of buspirone (BuSpar), a serotonin 5-HT1A receptor agonist, in the treatment of anxiety disorders
Current hypotheses posit serotonin excess as a cause of both positive and negative symptoms in schizophrenia. The robust serotonin antagonist activity of clozapine and other second-generation antipsychotics, coupled with the effectiveness of clozapine to decrease positive symptoms in chronic patients has contributed to the validity of this proposition.
There is weak evidence for the significant involvement of serotonin in ADHD. The support for the serotonin hypothesis comes from the fact that some drugs (TCA & MAOI) that affect serotonin metabolism are moderately effective in ADHD. However SSRIs have not been shown to be effective. Thus, if serotonin plays a role in ADHD, it is not likely to have a central role but rather an adjunctive role to one or more other neurotransmitter systems.
SSRIs can cause anorgasmia, erectile dysfunction, diminished libido. Stimulation of postsynaptic 5-HT2 and 5- HT3 receptors =decreases dopamine release from the substantia nigra =Sexual Dysfunction.
Low CSF serotonin metabolites often found in certain depressions. Also are found among people who have made suicide attempts who are violent, impulsive, alcoholics and it has been found among their relatives . Impulsive alcoholic violent offenders have decreased 5-HIAA.
Seretonin in ANOREXIA NERVOSA Three neurotransmitters involved in regulating eating behavior in the paraventricular nucleus of the hypothalamus. Serotonin, Dopamine, Norepinephrine. Seretonin in BULIMIA NERVOSA Because antidepressants often benefit patients with bulimia nervosa and because serotonin has been linked to satiety, serotonin and norepinephrine have been implicated.
Studies of personality traits and the dopaminergic and serotonergic systems indicate an arousal- activating function for these neurotransmitters. Raising serotonin levels with serotonergic agents such as fluoxetine (Prozac) can produce dramatic changes in some character traits of personality. In many persons, serotonin reduces depression, impulsiveness, and rumination, and can produce a sense of general well-being.
One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Because of serotonins growth- promoting effect on cardiac myocytes, persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.