Serotoniergic neurotransmission

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Published on March 19, 2009

Author: dhirajsona

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Serotonergic Neurotransmitter :  Serotonergic Neurotransmitter Maj Dhiraj Raja Serotonin And Acetylcholine:  Serotonin And Acetylcholine Introduction Serotonin Synthesis, Release, & Inactivation Oraganization & Function of the Serotonergic System Psychopathology & Psychopharmacology Introduction….:  Introduction…. The Serotonergic system is known to modulate mood, emotion, sleep and appetite and is implicated in the control of behavioral and physiological functions. Introduction:  Introduction In the early 20th century, Physiologist were unsure about Neurocommunication In 1920 Otto Lowei, a German Pharmacologist carried out 1st Experiment and introduces one of the body’s great system,Cellular communication, The system of Synaptic Transmission Introduction:  Introduction Serotonin is one of the most powerful neurotransmitters, with widespread effects. It can elevate mood and produce a sense of well-being. It was first recognised as a powerful vasoconstrictor in blood serum.  Isolated in 1948 by Page , was later found to be associated with the central nervous system.   Introduction:  Introduction 1990 was the “Decade of Serotonin” Has been featured as the culprit in just about every Human Malody,Including Depression,Anxiety,Obesity,Impulsive Aggression & Violence, and even Drug Addiction Seratonin Synthesis:  Seratonin Synthesis Regulated by the activity of tryptophan hydroxylase & the availability of the serotonin precursor tryptophan Serotonin Synthesis:  Serotonin Synthesis Serotonin synthesis in brain stimulated by large dose of tryptophan Link between food intake & 5-HT synthesis-John Fernstorm & Richard Wurtman,1972 Serotonin Synthesis:  Serotonin Synthesis 1.Do the dietary effect observed in rats also occur in Humans eating Typical meals? Wurtman & colleagues(2003) Addressed this issue by mesuring Plasma ratio of Tryptophan to large Amino acids in Subjects 2.Rapid Tryptophan depletion leads to Symptom relapse in recovered in depression patient-Smith et al,1997 Process of storage:  Process of storage Serotonin is transported into synaptic vesicle using vesicular transporter, VMAT2(vesicle monoamine transporter) The VMAT Resperine depletes Serotonergic Neurons of 5-HT Slide11:  3,4 methylenedioxymethamphetamine-MDMA Process of Release:  Process of Release Nerve impulse RELEASE DIRECTLY STIMULATED BY AMPHETAMINE FAMILY Process of Inactivation I:  Process of Inactivation I Process of Inactivation II:  Process of Inactivation II Organization of the Serotonergic System:  Organization of the Serotonergic System Major site of Serotonergic cell bodies is in the Upper pons and mid brain Median doral raphe nuclei and to a lesser extent the caudal locus ceruleus, the area postrema, and the interpedununcular area These neuron project to the basal ganglia ,the limbic system and the cerebral cortex. Organization of the Serotonergic System:  Organization of the Serotonergic System Organization of the Serotonergic System:  Organization of the Serotonergic System Interesting properties of serotonergic neurons in Dorsal Raphe- Exp. on Cat by Barry Jacobs What do these changes in Serotonergic activity mean for the Animal ? 5-HT facilitate the output of motor system in Brain –Jacob & Fornal(1993) Serotonin Receptors:  Serotonin Receptors Serotonin Receptors:  Serotonin Receptors Ionotropic & Metabotropic Receptors 5-HT1 Receptors-1A, 1B, 1D(Negatively coupled to cyclase via G1)00 -1B/1D Antagonist to treat Migraine 5-HT2 Receptors-2A,1B,1C(coupled via Gq to PLC) 5-HT3 Receptors-Heteroteterameric ionotropic receptors -5-HT3 antagonist as anti-emetics 5-HT4,5-HT6,5-HT7-Positively coupled to cyclase via Gs Serotonin deficiency signs/symptoms: :  Serotonin deficiency signs/symptoms: Depressed Nervous/anxious Worrier Fears/phobias Negative/pessimistic Irritable/impatient/edgy Obsessive compulsive tendency Serotonin deficiency signs/symptoms: :  Serotonin deficiency signs/symptoms: Think about the same things over & over again Self destructive or suicidal thoughts/plans Low self esteem/confidence Rage/anger/explosive behavior/assaultive Sleep problems/light sleeper Feel worse in & dislike dark weather Serotonin deficiency signs/symptoms: :  Serotonin deficiency signs/symptoms: Crave sugar/carbohydrates/alcohol/marijuana Use these substances to improve mood & relax Chronic pain (e.g. headaches, backaches, fibromyalgia) PMS Antidepressants or 5-HTP improve mood Family history of depression/anxiety/OCD/eating disorders Factors which reduce serotonin levels: :  Factors which reduce serotonin levels: Stress PCB’s, pesticides and plastic chemicals exposure Under-methylation Inadequate sunlight exposure Tryptophan (precursor) deficiency Iron, calcium, magnesium, zinc, B3, B6, folate & vitamin C deficiency Inadequate sleep Factors which reduce serotonin levels: :  Factors which reduce serotonin levels: Glutathione deficiency Chronic infections Food allergies Genetic serotonin receptor abnormalities Chronic opioid, alcohol, amphetamine & marijuana use Human growth hormone deficiency Progesterone deficiency Impaired blood flow to brain Insulin resistance or deficiency Serotonin and Psychopathology:  Serotonin and Psychopathology Serotonin occurs naturally in the body. In the periphery, serotonin acts both as a gastrointestinal regulating agent and a modulator of blood vessel tone although only 2% of the body’s serotonin is found in the brain as a neurotransmitter Serotonin content of various body fluids including CSF, platelets and plasma has been studied (Leonard, J.Clin Psy 2000 61:12-17) Serotonin and Psychopathology:  Serotonin and Psychopathology  Psychiatric disorders including depression, anxiety, aggression, compulsive behavior, substance abuse, bulimia, seasonal affective disorder, childhood hyperactivity, mania, hyper sexuality, schizophrenia, and behavioral disorders have been associated with impaired central serotonin function. Serotonin and Psychopathology:  Serotonin and Psychopathology Rapid lowering of tryptophan increases impulsiveness and decreases discriminating ability in normal individuals. The effect of 5-HT depletion on discriminating ability is similar to that reported in depressed patients. Role of Serotonin in Anxiety:  Role of Serotonin in Anxiety Is based to a large extent on the effectiveness of various drug treatments SSRIs desensitize terminal 5-HT autoreceptors (but not 5-HT2) in orbitofrontal cortex more 5-HT is released to act on postsynaptic 5HT2 receptors-Biler and Montigny,1999 Chronic Rx with Buspirone produces down regulation of both 5-HT1A receptors and 5-HT2 receptors in selected brain areas-Charney et al 1990 Serotonin and Depresion:  Serotonin and Depresion In 1965, Joseph Schildkraut put forth the hypothesis that depression was associated with low levels of norepinephrine, and later researchers theorized that serotonin was the neurotransmitter of interest. Decrease in Plasma Tryptophan contribute to the Depression-Cowen 2005. Slide32:  Serotonin is slightly lowered in dysthymic and endogenous depressed patients Peripheral abnormalities in serotonin metabolism occur in melancholic patients Serotonin and Depresion DSH and Serotonin :  DSH and Serotonin Low CSF Concentration of the serum metabolites 5 HIAA was reported to be associated with higher lifetime aggressivity, impulsivity and greater suicidal intent in patients with major depressive disorders –Placidi et al.,2001 Post-mortem brain studies suggested that suicide victim have increased expression of 5-HT 2A rceptors & decrease in 5-HT transporter in pre-frontal cortex-Stockmeier,2003 DSH and Serotonin:  DSH and Serotonin Brain serotonin levels as a predictor of suicide has been the subject of intense research scrutiny over the past several years (Lacasse JR, 1. PL0S Med 2005, 2;12: 392) OCD and Serotonin:  OCD and Serotonin OCD symptoms respond to drugs that affect 5-HT function suggest that 5-HT function might be abnormal in OCD. Molecular genetics studies found association between OCD and genes coding for 5-HT1D receptor-Mundo et al.,2002 Schizophrenia and serotonin:  Schizophrenia and serotonin Hallucinogen LSD is an agonist at 5-HT2 recpts Positive correlation between 5-HIAA in CSF and Negative symptoms,which would suggests that increased 5-HT function is associated with symptoms-Csernansky and coworkers,1990 Schizophrenia and serotonin:  Schizophrenia and serotonin 5-HT 2 receptors antagonism may add to the atypical profile of some antipsychotics (clozap,Resperidone,Quetiapine,Ziprasidone, Aripiprazole-Meltzer,2004,Kane et al 1988),& allelic variation in 5-HT2A gene may be a minor risk factor for schizophrenia expression of frontal cortex 5-HT 2A receptors in both post-mortem & functional imaging studies-Dean,2003 Eating Disorder and Serotonin:  Eating Disorder and Serotonin Neuroendocrine challenge tests & brain imaging studies suggest that brain 5-HT function is abnormal in Bulimia Nervosa-Kaya et al 2001 Fibromyalgia Syndrome    :  Fibromyalgia Syndrome    Increase in CSF substance P and decrease in serum and CSF serotonin (Loeser et al, 2001; Portenoy  et al, 1996; Wall et al, 1994)  Serotonin and Aggression  :  Serotonin and Aggression  Animal studies  - inverse relationship between 5-HT and aggression e.g. Higley et al. 1992 - rhesus monkeys   Inverse relationship between CSF 5-HIAA and history of aggression e.g. Brown et al. 1985  Addiction and serotonin:  Addiction and serotonin Alcoholism, drug use disorders and cigarette smoking are all associated with higher suicide rates. Low serotonin activity may favor addictive behaviors and independently predispose to suicidal and aggressive acts. Some drugs can deplete or lower serotonin further.   Alcoholism and Serotonin:  Alcoholism and Serotonin Decreased Serotonin in Alcoholics SSRIs may improve drinking outcome in Type I alcohol dependant but may worsen outcome in Type II alcohol dependence-Lingford-Hughes et al 2004 Rx of Serotonin Def Syndrome:  Rx of Serotonin Def Syndrome Slide45:  Fluxoteine Paroxetine Sertralline Citalopram Serotonin Syndrome:  Monoamine oxidase inhibitors in combination with TCAs.SSRIs Meperidine,Dextromethorphan Monotherapy with SSRI TCAs in combination with SSRIs Opiate analgesics in combination with SSRIs,Venelafaxine, Mitrazepine Sumatriptan and SSRIs,MAOIS Herbal products(St John’s wort) and SSRIs Tramadol in combinaation with venelafaxine,mitrazepine Atypical antipsychotics and serotonergic antidepresant Boyer EW Shaon M.The serotonin syndrome.N Engl J Med.2005:352(11) Beier M.The serotonin syndrome revisited.JAMDA2005:6(4):281 Serotonin Syndrome CONCLUSION:  CONCLUSION References:  References Psychopharmacology-Jerrold,Meyer CTP Short Text Book Oxford Synopsis of Psychiatry Slide50:  With repeated administration, the auto Receptors become less sensetive & their inhibition of serotonergig neurons decreases Which leads to an increase in 5-HT function and 5-HIAA. The desensitization of the autoreceptors coincides with the onset of clinical effectiveness . Slide51:  The initial effect of reuptake blockade include increased 5-HT in the synapse & activity at both postsynaptic receptors 7 auto receptors. Auto receptors activation reduce the rate of firing of the cell as well as The rate of synthesis 7 release of 5-HT & subsequently also reduces the rate of formation of 5-HIAA

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