1 / 72

90% OF TOTAL BODY SEROTONIN IS FOUND IN GUT. 8% OF TOTAL FOUND IN PLATELETS

SEROTONIN . 90% OF TOTAL BODY SEROTONIN IS FOUND IN GUT. 8% OF TOTAL FOUND IN PLATELETS 1-2% OF TOTAL FOUND IN PINEAL GLAND (WHICH IS NOT REALLY PART OF CNS) < 1% LIVES IN THE RAPHE NUCLEI IN RETICULAR REGION OF BRAIN STEM.

takara
Download Presentation

90% OF TOTAL BODY SEROTONIN IS FOUND IN GUT. 8% OF TOTAL FOUND IN PLATELETS

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. SEROTONIN 90% OF TOTAL BODY SEROTONIN IS FOUND IN GUT. 8% OF TOTAL FOUND IN PLATELETS 1-2% OF TOTAL FOUND IN PINEAL GLAND (WHICH IS NOT REALLY PART OF CNS) < 1% LIVES IN THE RAPHE NUCLEI IN RETICULAR REGION OF BRAIN STEM. RAPHE INNERVATES SPINAL CORD AND ASCENDS INTO THE CEREBRAL HEMISPHERES

  2. From Raphe

  3. RAPHE NEURONS HAVE REGULAR SLOW SPONTANEOUS FIRING RATE (0.5 TO 2.5 SPIKES/SEC) FUNCTION: NO INFORMATION TRANSFER, ONLY MODULATION OF OTHER SYSTEMS. 5HT APPLIED TO RAPHE NEURONS DECREASES FIRING.  SPONTANEOUS ACTIVITY IS ELIMINATED DURING REM SLEEP. Active Quiet SWS REM

  4. Serotonin Production Tryptophan is a precursor from diet. Uptake depends upon level of other amino acids in blood/diet. High carbohydrate diet enhances tryptophan uptake. Low intake of tryptophan leads to low levels of serotonin in CNS – this can produce irritability, aggressive behaviors and depression 1% of ingested tryptophan is converted to serotonin in the brain. Uptake into CNS is via active, high‑affinity transport. Metabolism: converted to 5HTP by tryptophan hydroxylase.

  5. SYNTHESIS OCCURS IN TERMINALS. TH IS NOT SATURATED WITH SUBSTRATE. 5HTP CONVERTED TO SEROTONIN BY DECARBOXYLASE. 

  6. Dietary tryptophan depletion leads to symptom relapse in recovered depressed patients

  7. TERMINATION OF ACTION PRIMARILY BY RE-UPTAKE

  8. 5HT1-A RECEPTORS ARE AUTORECEPTORS ON RAPHE NEURONS MORE SENSITIVE TO LSD THAN TO 5HT! THESE RECEPTORS ARE TARGETED TO RELIEVE ANXIETY

  9. 5-HT1-A receptors control the release of serotonin and activity of 5HT neurons via intracellular signaling mechanisms

  10. Genetic deletion of the 5-HT1A receptor increases anxiety-like behavior in mice

  11. Ratings of religiosity & spirituality inversely correlated with the number of Serotonin 5-HT1A receptors in humans American Journal Psychiatry 160:1965-1969, November 2003

  12. Stimulating 5HT-1A receptors with BuSpar relieves anxiety

  13. Hallucinogens, e.g. LSD, Turn Off Serotonergic Neurons in the Raphe Nuclei by Stimulating Serotonin Receptors

  14. Neuronal circuits implicated in the responses induced by psychoactive chemicals. 5-HT2A–Glutamate receptor complex expressed by cortical pyramidal neurons represents the target of LSD-like psychoactive drugs that will dysregulate the signaling properties of cortical pyramidal neurons and affect cognition and perception processes in the brain cortex. TINS, 2009.

  15. How is LSD able to do this? TH Serotonin contains an indole ring with a carbon chain attached

  16. ….So do these hallucinogens LSD Psilocybin Hallucinogens produce synesthesia.

  17. Synesthesia: a remarkable, rare condition where an individual has multimodal perceptual experiences from a unimodal sensoryevent. The ability of hallucinogens to induce synesthesia may be related to their ability to influence serotonergic control over the frontal lobes.

  18. “Using diffusion tensor imaging, we have shown for the first time that the extraordinary sensory experiences in synesthesia are associated with abnormalities in white matter structure.”

  19. HALLUCINOGENS"IT IS REMARKABLE THAT ONE CHARACTERISTIC WHICH SEEMS TO SEPARATE MAN FROM THE ALLEGEDLY LOWER ANIMALS IS A RECURRING DESIRE TO ESCAPE FROM REALITY" C.H.W. HORNE, 1963.IN 1990, A NIDA SURVEY REVEALED THAT BETWEEN 17 AND 21 MILLION PEOPLE IN THE US HAD USED A HALLUCINOGEN AT LEAST ONCE THAT YEAR. "A PSYCHEDELIC EXPERIENCE IS A JOURNEY TO NEW REALMS OF CONSCIOUSNESS.  THE SCOPE AND CONTENT OF THE EXPERIENCE IS LIMITLESS, BUT ITS CHARACTERISTIC FEATURES ARE THE TRANSCENDENCE OF VERBAL CONCEPTS, OF SPACE‑TIME DIMENSIONS, AND OF THE EGO AND IDENTITY."  TIMOTHY LEARY, 1964.

  20. One function of consciousness is to filter out the overwhelming and confusing mass of sensory input our brain receives.The use of hallucinogens therefore usually occurs in structured and protected settings. It should come as no surprise when I occasionally describe how strict religious and social rules have been drawn around the use of agents that alter perception. HALLUCINOGENS

  21. These drugs produce a surprisingly similar consensus of seeing geometric images accompanied by altered feelings. • There were four consistent geometric images reported: • a lattice or grating • a cobweb structure • a tunnel or funnel alley • spiral images. • Though colors varied, participants consistently reported brightness intensification. Moreover, the apparent size, geometrical shapes, and symmetry were strikingly similar from participant to participant (Kluver, 1928).

  22. 62-72% of 500 participants tested with LSD reported similar simple forms at low doses. 72% reported religious symbols and images 49% reported small animals and humans. Images tended to pulsate and move toward a center tunnel or away from a bright center (a phenomenon similar to reported near death experiences). Unlike psilocybin-induced hallucination, these visions could not be consciously controlled.

  23. HALLUCINOGENS AND RELIGION In Central and Southern America, use of psilocybin mushrooms was a common religious practice. The mushroom is known as a sacred mushroom and was considered a religious path to the spirit world. Mushroom art and sculptures exist from 1000 BC on stones that had religious meaning. The Codex Vienna Mixtec manuscript (13th century) depicted the ritual use of the mushrooms by the Mixtec Gods.

  24. PSILOCYBIN CAN BE FOUND IN MORE THAN 75 DIFFERENT SPECIES OF MUSHROOMS. PSILOCYBEMEXICANA IS THE MOST FAMOUS ORAL DOSE: 2 TO 4 MUSHROOMS (DEPENDS UPON WHICH MUSHROOM IS THE SOURCE OF THE DRUG).  LATENCY: 30 MIN. PEAKS AT 90 MIN.  EFFECTIVE DOSE: 4 MG P.O.; 1/100 AS POTENT AS LSD. DURATION: 6 HOURS. MINOR PHYSICAL CHANGES: DRY MOUTH, SLIGHT NAUSEA, DILATED PUPILS. VIOLENT NAUSEA AND VOMITING WELL ABSORBED FROM GI TRACT.

  25. 1570'S FRANCISCO HERNANDEZ DOCUMENTED CENTRAL AM. INDIANS USE OF THESE MUSHROOMS (THEIR CORNUCOPIA INCLUDED USE OF 1200 HERBAL REMEDIES). TEONANACATL "GOD'S FLESH" "SACRED MUSHROOM" ALBERT HOFMANN 1958 ISOLATED ACTIVE INGREDIENT. (ALSO OF LSD FAME). HE INGESTED 32 DRIED MUSHROOMS TO DETERMINE THEIR EFFECTS. HE CLAIMED THAT THE EXPERIENCE WAS SIMILAR TO HIS LSD EXPERIENCE. PSILOCYBIN IS CONVERTED INTO PSILOCIN WHICH IS MORE LIPID SOLUBLE AND THE ACTUAL PSYCHOACTIVE AGENT. MUSHROOMS ARE EATEN RAW, COOKED INTO ANY RECIPE THAT CALLS FOR MUSHROOMS OR STEEPED INTO A TEA. THE POWDER IS EATEN, INSUFFLATED (BREATHED THROUGH THE NOSE) OR SWALLOWED IN GELATIN CAPSULES.

  26. MECHANISM: AGONIST AT 5HT-1A AND 5HT-2A RECEPTORS. EXPERIENCE: RELAXATION, EUPHORIA, INTROSPECTION, DETACHMENT.  HIGH DOSES: LSD‑LIKE CHANGES. ALTERED PERCEPTION OF SENSORY STIMULI. AUDITORY AND VISUAL HALLUCINATIONS. ELEVATED MOOD, GREAT HILARITY.  UNREAL HALLUCINATIONS ARE RECOGNIZED AS SUCH BY USERS. Side Effects: PHOTOSENSITIVITY, MUSCLE WEAKNESS, VERTIGO OVERDOSE: HYPERTHERMIA, FLUSHING, CONVULSIONS, ANXIETY, PANIC REACTIONS, PARANOIA. DEATH CAN OCCUR FROM INGESTING ABOUT 2000 TIMES THE NORMAL DOSE.

  27. 25% OF DOSE IS EXCRETED UNCHANGED BY KIDNEYS INTO URINE. INACTIVE METABOLITES REMAIN IN BODY FOR MANY DAYS. DEPENDENCE: NO PHYSICAL OR PSYCHOLOGICAL SEEN. TOLERANCE: NOT LIKELY DUE TO OCCASIONAL USE TIMOTHY LEARY'S GOOD FRIDAY TEST IN 1962 20 SEMINARIANS, DRUG/NO DRUG (30 mg PSILOCYBIN) ATTENDED RELIGIOUS SERVICE.  CLAIMED THAT THE USING THE WOULD ENHANCE MYSTICAL EXPERIENCE. 

  28. R. R. Griffiths &W. A. Richards & U. McCann & R. Jesse, Johns Hopkins University School of Medicine, Psychopharmacology (August, 2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. “psilocybin occasioned experiences similar to spontaneously occurring mystical experiences … which were evaluated by volunteers as having substantial and sustained personal meaning and spiritual significance. The ability to [induce] mystical experiences should permit rigorous scientific investigations about their causes and consequences, providing insights into underlying brain mechanisms…”

  29. D‑LYSERGIC ACID DIETHYLAMIDE, LSD LSD IS ERGOT DERIVATIVE OR INDOLE ALKYLAMINE THE HALLUCINATIONS PRODUCED BY THIS DRUG CAN BE ATTENUATED BY 5-HT-2 RECEPTOR ANTAGONISTS. THEIR HALLUCINOGENIC POTENCY IN HUMANS CORRELATES WITH THEIR AFFINITY FOR A FEW DIFFERENT 5HT SITES. HALLUCINOGENS ACT AS AGONISTS AT MANY DIFFERENT RECEPTORS. INGESTED ORALLY; LSD IS RAPIDLY ABSORBED. DOSE: 100 UG,P.O. IS HALLUCINOGENIC. 0.3 UG/KG IS SUBJECTIVELY DETECTABLE; 50 UG, I.V. EFFECTIVE ONLY ABOUT 1% REACHES THE BRAIN: CONCENTRATES IN VISUAL CORTEX, LIMBIC SYSTEMS, RETICULAR FORMATION. METABOLIZED RAPIDLY BY LIVER; EXCRETED BY KIDNEYS AS 2‑OXY‑LSD. TOLERANCE AND CROSS‑TOLERANCE DEVELOPS WITHIN 3‑4 DAYS WITH CONTINUAL USE.  PSYCHODELIC EFFECTS SHOW TOLERANCE AS WELL. DEPENDENCE: NO PSYCHOLOGICAL OR PHYSIOLOGICAL DUE TO TYPICALLY INFREQUENT USE

  30. LSD Latency is about 30 - 90 min. Half‑life is about 3 hrs.  Psychic effects are maximal at 1 to 3 hours. At which time virtually no radioactively-labeled LSD is in the brain! The drug sets in motion a cascade of events that may involve entire brain. Serotonergic system may act as trigger. Duration: 8 to 12 hours. Metabolized by the liver almost entirely. Metabolites are excreted in the bile and feces. Physiological effects: sympathomimetic ‑due to Raphe cell projections to spinal cord onto pre‑ganglionic autonomic nervous system cells. 

  31. USE CORRELATES WITH DECREASED RAPHE CELL FIRING AND INCREASED LEVELS OF 5HT AND DECREASED LEVELS OF THE METABOLITE 5HIAA. Why? Do we see more 5HT and less 5HIAA? BEHAVIORAL EFFECTS GREATLY OUTLAST THE SLOWING OF RAPHE FIRING. BEHAVIORAL EFFECTS SHOW TOLERANCE - SLOWING OF RAPHE FIRING DOES NOT. DESTRUCTION OF 5HT NEURONS ACTUALLY ENHANCES LSD'S EFFECTS. using LSD with MDMA (candy-flipping). hippy flipping - pairing psychedelic mushrooms kitty flipping - ketamine and ecstasy candy flipping on a string – cocaine + LSD + MDMA. candy flips - home-made capsules containing LSD + MDMA

  32. Hallucinations - mechanism?? Unknown... But... Releases post‑synaptic cells in cortex and subcortical areas from inhibition. Many of these cells are in visual processing systems, e.g. Lateral geniculate and limbic structures.  Perceptual effects are like watching own private TV. User is aware that he is seeing hallucinations, that they are not real, but is powerless to stop them. Synesthesia – sensory system cross-over of information processing. Vivid swirling colors, sounds have colors, intensification of visual perception.  Lowered pain sensitivity.  Possibly due to changes in activity of the 5HT fibers that descend into the spinal cord. Withdrawal. No serious withdrawal symptoms.

  33. Adverse effects.  Chromosome damage.  Original studies were performed badly, poorly controlled, experimenter bias, populations observed were too small.  Chromosome breakage rates may be higher in LSD users or else people who have endogenously high breakage rates like to take LSD.  Most recent studies show no effect of LSD on chromosomes. Acute panic reactions. Bad experience with LSD; problem is that it cannot be terminated by user... Leads to panic.  Increased suicides associated with use, however no cause and effect is believed to exist. Adverse reactions more often seen with poorly adjusted users.

  34. Flashbacks.  Sudden and "unexpected" recurrences of aspects of earlier drug experience.  2256 army enlisted men, 23% reported flashbacks, compared to 5% for amphetamine and 1% for marijuana.  Not dangerous, are often self‑induced! Occurs during high stress, e.g. Driving Or just before going to sleep Suggests that some permanent changes in brain function occurred Effects on temperature and time estimation. LSD, mescaline, and psilocybin all elevate body temperature (sympathetic side effect).  All are associated with overestimation of time (time moves faster for them.) Expt. Count to 60, one count each second.  These drugs cause faster counting.  Infrared lamps cause faster counting in un-drugged subjects. 

  35. D‑lysergic acid monoethylamide (a less lipid version of LSD) may be responsible for Salem witchcraft crisis that began in December of 1691. Eight girls suffered with distempers = Disorderly speech, odd postures and gestures & convulsive fits. Lacking a reasonable explanation the New England puritans saw this as the work of Satan brought about by the practice of witchcraft by “some women of ill repute.” By September 1692 19 men and women were hung, one man was pressed to death and two died in prison. POISONING IS CALLED ERGOTISM AND CAUSES A BURNING IN THE EXTREMITIES DUE TO VASOCONSTRICTION OF BLOOD VESSELS. CAN LEAD TO LIMB DEATH. 40,000 DEATHS IN AD 944 EUROPE “SAINT ANTHONY’S FIRE.”

  36. Ergot fungus (Claviceps purpurea) growing on corn

  37. MORNING GLORY RIVEACORYMBOSA:  KNOWN AS OLOLIUQUI BY THE AZTECS. DRAWINGS FROM THE 16th CENTURY SUGGESTED THE MORNING GLORY WAS OLOLIUQUI. BUT IT WAS NOT UNTIL A PLANT WAS DISCOVERED STILL GROWING IN 1939 IN A ZAPOTEC INDIAN GARDEN IN OAXACA MEXICO WAS THIS CONFIRMED. CONTAINS D‑LYSERGIC ACID MONOETHYLAMIDE;  ONE‑TENTH AS POTENT AS LSD. WHY? DISCOVERED BY ALBERT HOFMANN.  ORALLY EFFECTIVE. REQUIRES 100‑150 MORNING GLORY SEEDS TO GET HIGH.  CAUSES A DREAMY STATE WITHIN ABOUT 20 MINUTES, FOLLOWED BY SLEEP.

  38. Does not produce the visual hallucinations seen with LSD. Often taken while alone. 16th century Mexico: morning glory seeds had most religious signi­ficance. A.K.A. Mexican bindweed or "flower of the virgin" Other variations on this plant that became popular in US in 1960's include "Heavenly blue, pearly gates & wedding bells"

  39. HAWAIIAN WOOD‑ROSE SEEDS (Argyreia Nervosa) BIOCHEMISTRY: SAME AS MORNING GLORY REQUIRES 4 TO 8 WOOD‑ROSE SEEDS TO GET HIGH Many experience nausea and gas. WHY? The fuzzy husk of the seed is often removed and not ingested because it seems to worsen the nausea. Seeds contain D‑LYSERGIC ACID MONOETHYLAMIDE

  40. DMT.  N,N‑DIMETHYLTRYPTAMINE LSD‑LIKE DRUG. SHORTER DURATION OF ACTION. ALSO HAS MAO-I ACTION. DMT DETERIORATES RAPIDLY, ESPECIALLY IN THE STOMACH LATENCY: 10 ‑ 15 MIN WITH I.M. DOSE.; 2 ‑ 3 MIN WITH INHALATION.  DURATION: 10 MINUTES.  "BUSINESSMAN'S TRIP". EFFECTIVE HALLUCINOGENIC DOSE ‑ 1 MG INHALATION PRODUCES EUPHORIA, BEHAVIORAL EXCITEMENT AND HALLUCINATION WITH EYES OPEN OR CLOSED!

  41. MACROPSIA IS COMMON (APPARENT MAGNIFICATION OF OBJECTS). SE‑ TACHYCARDIA, HYPERTENSION, MYDRIASIS, ACUTE ANXIETY ATTACKS, PANIC REACTIONS TOXICATION: NUMBNESS OF LIMBS, TWITCHING OF THE FACE, LACK OF MOTOR CONTROL, NASAL DISCHARGES, NAUSEA, VOMITING. NO EVIDENCE FOR PHYSIOLOGICAL OR PSYCHOLOGICAL DEPENDENCE TOLERANCE NOT LIKELY; NO CROSS‑TOLERANCE WITH LSD

  42. DMT FIRST SYNTHESIZED IN 1931, ABUSE BEGAN IN 1956. DMT: WORLDWIDE, THIS IS THE MOST IMPORTANT NATURALLY OCCURRING HALLUCINOGENIC AGENT.  [S. AM. INDIANS USE IT AS COHOBA OR VIROLA SNUFF.] A BLOOD-RED RESIN IS BOILED OUT OF THE BARK OF THE VIROLA TREE (FOUND IN JUNGLE) THEORY ONCE BELIEVED TO BE AN ENDOGENOUS SCHIZOPHRENIC AGENT. ENZYME THAT CONVERTS TRYPTAMINE TO DMT IS FOUND IN THE HUMAN BRAIN. BUT...NO EVIDENCE THAT IT HAPPENS YET. LOW LEVELS OF DMT HAVE BEEN FOUND IN BRAIN OF NORMALS AND SCHIZOPHENICS. DMT AND DET NOT ORALLY ACTIVE.

  43. PHENCYCLIDINE PIPERIDINE HCL.  (PCP, ANGEL DUST) SYNTHESIZED: 1957, USED AS DISSOCIATIVE ANESTHETIC, HAD LIMITED RESPIRATORY DEPRESSION. EMERGENCE PSYCHOSIS IN PATIENTS! ABUSE BEGAN IN 1965. ORALLY ACTIVE.  PCP IS USUALLY SMOKED ON CIGARETTES THAT HAVE THICK WRAPPERS TO ABSORB THE PCP LIQUID. USE LEADS TO PSYCHOTIC STATE.  CNS DEPRESSANT‑ DEATH BY CARDIAC ARREST.

  44. DOSE: 2 ‑ 10 MG P.O. HIGH DOSE - SEDATIVE; LOW DOSE - STIMULANT = IN RATS. LATENCY 1 HR., PEAK EFFECTS IN 5 HRS. DURATION: 12 HRS. FOLLOWED BY DEPRESSION THAT MAY LAST UP TO 24 HOURS. METABOLISM: ALMOST ENTIRELY BY LIVER, EXCRETED BY KIDNEYS. EXPERIENCE: CHANGES IN BODY IMAGE, RELAXATION, TINGLING FEELING, FEELINGS OF ISOLATION AND FLOATING IN SPACE, SLOWING OF MENTAL PROCESSES. MORE INTENSE THAN LSD, BUT MUCH SHORTER. 

  45. PHARMACOLOGY CNS DEPRESSANT, ANESTHETIC, TRANQUILIZER, PSYCHEDELIC.  RESEARCH SUGGESTS AND ENDOGENOUS PCP RECEPTOR AND LIGAND. "ANGELDUSTIN" HAS SOME AMPHETAMINE-LIKE BEHAVIORAL EFFECTS. TOLERANCE. DEVELOPS IN CHRONIC USERS.  MILD WITHDRAWAL SYMPTOMS. INCLUDING, DIARRHEA, SLEEPINESS, RARELY CONVULSIONS.

  46. PCP blocks Calcium ion entry via the NMDA glutamate receptor channel

  47. Dysregulation of the signaling processes of cortical pyramidal neurons impairs cognition and normal perception in the cortex.

More Related