4-19-10 The Nervous System - Chemical Information-color

4-19-10 The Nervous System - Chemical Information-color -...

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Unformatted text preview: Clicker Question If the membrane potential were based solely on the K+ concentrations, according to the Nernst equation (V = (kT/ze)ln ([K+out]/[K+in])), which K+ (V distribution would give the most negative membrane potential (V)? A) ([K+out]/[K+in]) = 100/1 B) ([K+out]/[K+in]) = 10/1 C) ([K+out]/[K+in]) = 1/1 D) ([K+out]/[K+in]) = 1/10 E) ([K+out]/[K+in]) = 1/100 You Worked Hard! You Worked Hard! Where are we? Last time I discussed… the the structure of neurons, the arrangement of neurons and glial cells and the blood-brain barrier. bloodthe the electrical properties of cells. how how neurons generate action potentials that rapidly transmit information throughout the body. multiple multiple sclerosis. synapses, synapses, EPSP and IPSP. botulism botulism and Botox. The Body as an Industrial Palace Digestion and absorption are physicophysico-chemical processes. The circulation of the blood is a circulation physicophysico-chemical process. The burning of food to make ATP burning cois a physico-chemical process. Reproduction and development is a physico-chemical process. physicoThe replication and expression of replication DNA is a physico-chemical process. physicoThe generation of EPSP, IPSP and generation action potentials are physicophysicochemical processes. This time I will discuss… the the body as a physico-chemical machine. physicochemicals chemicals as informational molecules. how how neurotransmitters, their receptors, re-uptake proteins, and the reenzymes that degrade them regulate the pathway of electrical activity in the brain. drugs drugs that influence brain chemistry are used to treat mental illness. the the brain as 100 billion or more interacting chemical cauldrons. 1 The Body as a Physico-Chemical PhysicoMachine Chemical signals flowing through our blood stream as well as electrical signals passing along our passing along our neurons neurons and chemical signals passing across our synapses coordinate the movement of our muscles to allow our body to perform our everyday tasks. Rube Goldberg: How to Get Up for a 9 AM Class When Our Parts are Replaced with the Parts of Others, We Remain Ourselves The following parts can be replaced: heart, lung, kidney, liver, pancreas, islets of Langerhans, cornea, cornea, skin, bone, bone marrow, blood vessels, blood, hand, and face transplanted from other humans and heart valves transplanted from pigs. Face Transplant Face Transplant April, 2009 Monism (Materialism) or Dualism? Is the mind and body nothing more than a physicophysico-chemical machine composed of atoms atoms and held together by electromagnetic forces? A monist or materialist says yes. Is the mind nonmaterial? nonmaterial A dualist says yes. dualist 2 The Human Brain and Free Will Many chemical processes are taking place in 100 billion neurons and 1000s more excitatory and inhibitory synapses. In all cases, the physiological processes involve small numbers of molecules in small volumes. The small numbers leads to statistical variation and a lack of determinism and an appearance of appearance free will. Or is it possible that there still can be free will and thought energy controls what happens at thought controls the synapse? Upward and Downward Causation “I said to one of the scientists: ‘It seems very evident that due to changes in the chemical processes of the brain, many of our subjective experiences like perception and exper lik sensation sensation occur. Can one envision the reversal of this causal process? Can one postulate that pure thought itself could effect a change in the chemical processes of the brain?’” “The scientist’s response was quite surprising…it is not possible….” John John Eccles: Open Questions The majority of neurobiologists are materialists or monists materialists or monists who believe that the mind is determined solely by physicophysicochemical processes chemical processes. John John Eccles, like Wilder Penfield, is a dualist and dualist and feels like the question is still the open. He believes that our He strong intentions or will can lead to a change in brain chemistry or action at a given synapse. Informational Molecules The body produces a number of chemicals that inform cells about the status of the rest of the body. The endocrine glands endocrine produce informational molecules, called hormones hormones, which travel to the rest of the body through the blood stream and and maintain homeostasis, homeostasis, allostasis and their balance. Informational Informational Molecules The hormones are informational molecules that leave secretory cells secretory by exocytosis and enter the blood stream. Proteins in the blood plasma carry the hydrophobic hormones through the blood stream. Upon leaving the blood stream, the hydrophobic steroid hormones diffuse across the plasma membrane and bind to receptors inside the target cell. The hormone and receptor diffuse into the nucleus to influence gene expression. The other hormones, which are hydrophilic hydrophilic, bind to receptors on the plasma membrane and initiate signal transduction chains that lead to a response. 3 Hormonal Informational Molecules We Have Discussed So Far Secretin Secretin Insulin, Glucagon Calcitonin, Calcitonin, Parathyroid Hormone (PTH) Aldosterone Antidiuretic Hormone (ADH) (ADH) Erythropoietin (EPO) Adrenaline, Cortisol FSH, LH Estrogen, Progesterone, Testosterone, Androgens Human Human Chorionic Gonadotropin Oxytocin (Pitocin) Pitocin) Human Growth Hormone (HGH) Many of the Informational Molecules are Indirectly Regulated Through Releasing Hormones that Come from the Hypothalamus (a Part of the Limbic System of the Brain) The Hypothalamus Is an Endocrine Gland that Is in the Brain and Receives and Transmits Signals Along Nerves Neurosecretory Cells of the Hypothalamus Neurosecretory cells are modified neurons. Some extend from the hypothalamus to the posterior pituitary. These neurosecretory cells synthesize and secrete ADH and oxytocin into the posterior pituitary into the posterior pituitary, from which the hormones enter the blood. Other neurosecretory cells synthesize and secrete releasing releasing and inhibiting hormones into the pituitary pituitary portal vein system that carries the hormones in the blood to the anterior pituitary. anterior The Hypothalamus Also Sends Out Action Potentials Along Neurons to the Adrenal Medulla Via the Spinal Cord During Times of Stress The body is regulated through a close working relationship between the endocrine system, which is endocrine chemical, long-lasting and slow and the nervous longnervous system, which is predominantly electrical, transient and fast. 4 Johann Thudichum (1884): Ahead of his Time and Ignored—Insanity may be Related to Brain Ignored— Chemistry “Many forms of insanity are insanity unquestionably the external manifestations of the effects upon the brain substance of poisons poisons fermented within the body, just as mental aberrations accompanying mental aberrations accompanying chronic chronic alcoholic intoxication are the accumulated effects of a relatively simple poison….These poisons we shall…be able to isolate….And then will come…the crowning discoveries to which our efforts must ultimately be directed…the discoveries of the antidotes….” Sigmund Freud (1930): Insanity may be Related to Brain Chemistry “We know that the mechanisms of the psychoses are in essence not different from those of neuroses, but we do not have at our disposal the quantitative stimulation the quantitative stimulation necessary necessary for changing them. The hope of the future here lies in organic organic chemistry or the access to it through endocrinology. The endocrinology future is still distant, but one should study analytically every case of psychosis because this knowledge will one day guide the chemical chemical therapy.” Primary Messengers in the Brain It was originally thought that all brain signals must be electrical because electricity is the only electrical thing that moves fast enough (150 m/s) to act in the brain. It seemed that chemical signals would be too chemica slow. Hormones move by pressure flow (created by the contraction of the heart) relatively slowly (0.5 m/s) through the blood stream. Neurotransmitters would move even slower by diffusion (0.01 m/s) than hormones that move by pressure flow in the blood. But if the distance is small, slow may not be too slow… Einstein’s Random Walk Equation The time (t, in s) it takes for a substance to (t diffuse a given distance (x, in m) is: t = x2/(2D) D (in m2/s) is the diffusion coefficient of the substance. This equation tells us that the time it takes for a molecule to diffuse over a given distance (x) is proportional to the square of the distance (x2). square It would take a molecule 100 times longer to travel a distance that is only 10 times further. Diffusion Coefficient D = kT/(6πrHη) kT/(6 Boltzmann’s Constant (k) is 1.38 x 10-23 J/K J/K Temperature (T) is ~310 K Viscosity (η) of the cytoplasm is ~0.004 Pa Radius (rH) of typical neurotransmitter molecules is (r ~10-10 -10-9 m The diffusion coefficient (D) of low molecular mass molecules in the cell is typically between 0.5 and 5 x 10-10 m2/s. 5 As long as the distance is short, diffusion can be fast enough! If D = 10-10 m2/s, according to Einstein’s random walk equation, it would take 2-12.5 2microseconds microseconds to diffuse across a 20-50 20nm wide synapse. So So neurotransmitters would be efficient transmitting information across a synapse in the brain. A Paradigm Shift: Chemical Signals As Well As Electrical Signals Are Important in the Brain While the random walk equation was derived in 1905, it wasn’t until “the sixties” when people would take the idea of chemical chemical messengers messengers in the brain seriously. The discovery that chemicals are involved in mental and behavioral processes came from the field of psychopharmacology. Paradigm Paradigm Shifts in Science A Trip through Brain Research Now I am going to take you on a trip of scientific discovery which led to a paradigm shift that allowed us to think of the brain and mind in terms of chemistry. We will start by looking at how mental illness was treated before chemicals. I will discuss a proposed relationship between LSD will discuss proposed relationship between LSD and and schizophrenia that turned out to be tenuous. We will see how John Gaddum thought (and disproved) that schizophrenia is caused by an schizophrenia imbalance in serotonin. serotonin We will see how we came to realize that schizophrenia can be seen as having too much dopamine in the dopamine brain and Parkinson’s disease (and a virus-induced viruscoma) results from having too little dopamine in the brain. 6 Bedlam or Bethlehem: An Asylum Designed by Robert Hooke (1675) Shakespeare Wrote About Bedlam (Before it was Razed in the Fire of London) In Shakespeare’s Henry VI, Part II, The King says, “Ay, “Ay, Clifford; a bedlam and ambitious humour and ambitious humour makes him oppose himself against his king.” Clifford Clifford says, “To Bedlam “To with him! Is the man grown mad?” Statues of "raving" and "melancholy" madness Scene at Bedlam from The Rake's Progress by William Hogarth (1796) Dr. Dr. Monro (physician to Bedlam) examining the straight jacketed and disheveled Charles James Fox (1784) William Norris, shackled sitting upright on his bed at Bedlam (1838). 7 Tuileries Palace: A Model for Bedlam? http://www.archive.org/details/maritalpowerexem00pack http://www.archive.org/details/prisonershidden00pack Controversial Treatment and Therapies for Schizophrenia in 1930s Physical restraint in mental hospitals(→) After noticing that mentally disturbed patients being treated for morphine addition became tranquil after recovering from hypoglycemic shock, a coma producing hypoglycemic shock, hypoglycemic was induced with insulin. After After noticing that schizophrenia improved after epileptic seizures, seizures seizures were induced with Cardiazol. Modern electroconvulsive therapy (ECT) was given to a psychotic man found wandering in a railway station. It stopped his hallucinations and it was then tried on others. Controversial Treatment and Therapies: Insulin Shock Therapy Insulin shock therapy Controversial Treatment and Therapies: Electroconvulsive Therapy (ECT) Controversial Treatment for Schizophrenia in the 1940s After hearing that neurotic apes became less aggressive after getting frontal frontal lobotomies, Egaz Moniz developed the Moniz developed the technique technique for performing frontal lobotomies on schizophrenics and won the Nobel prize in 1949. In the United States, Walter Freeman performed thousands of lobotomies and became known as “the lobotomist.” lobotomist.” 8 http://www.pbs.org/wgbh/amex/lobotomist/program/ There was a need for a better way to treat schizophrenia and other mental illnesses…. http://www.pbs.org/wgbh/amex/lobotomist/bedlam/ 9 “Given the facts…the people of any state will rally, as have the common people of Ohio, to put an end to concentration camps that masquerade as hospitals and to make cure rather than incarceration the goal of their mental institutions. “ Willard Psychiatric Center (Willard State Hospital) Ovid, New York Synthesis of LSD While looking for a new drug that could be used to treat the respiratory system, Albert Hofmann (1938) isolated lysergic acid from the ergot of ergot rye (used as a patent medicine—ergotol) and medicine— converted it to lysergic acid diethylamide (LSD). LSD had no effect on the respiratory system in the animal models, but Hofmann accidentally accidentally got some on his hands and it entered his mouth. He wrote (April 16, 1943), “I was forced to stop “I my work….there surged upon me an work….there uninterrupted stream of fantastic images of extraordinary plasticity and vividness and accompanied by an intense, kaleidoscope-like intense, kaleidoscopeplay of colours.” colours.” www.archives.nysed.gov Lysergic Acid Diethylamide (LSD) 10 Experimenting on the Mind-Altering MindEffects of LSD In the 1950s, therapists, the Central Intelligence Agency (CIA) and the military began experimenting experimenting with the mindmind-altering properties of LSD. LSD Seems to Mimic Schizophrenia John Gaddum (1953) realized that LSD produced hallucinationhallucination-like and delusiondelusionlike experiences in people that like experiences in people that took took it. Since hallucinations and delusions were major symptoms of schizophrenia, schizophrenia LSD might LSD might give insight into the causes of psychosis. Serotonin is an Informational Molecule Gaddum saw the similarities in the structure of LSD LSD and serotonin and found that LSD prevented serotonin and serotoninserotonin-induced contraction of smooth muscle. (At the time serotonin had not been found in the brain, it was just a substance isolated from the intestinal intestinal tract that caused smooth muscle to contract.) Betty Twarog and Irvine Page (1953) discovered that serotonin was a constituent of mammalian brains. Mental Illness May Be Due to a Chemical Imbalance Gaddum proposed that schizophrenia is related to serotonin, but this hypothesis proved to be too simplistic since other other serotonin receptor inhibitors did not cause hallucinations. However, when Gaddum suggested that sugges th LSD LSD produces delusions and hallucinations because it blocks the action of serotonin, he also stated that serotonin “play[s] an “play[s essential part in keeping us sane.” Gaddum’s 20th century hypothesis led to the rebirth of John Willis’ 17th century idea that the brain is a cauldron of chemical brain reactions and mental illness may be due, in part, to an abnormality in brain chemistry. LSD and Popular Culture: Aldous Huxley 11 LSD and Popular Culture LSD and Popular Culture www.lysergia.com LSD LSD Chlorpromazine (A Neuroleptic) In 1952, chlorpromazine chlorpromazine (Thorazine), an antiemetic drug that Thorazine), was used for motion sickness was accidentally accidentally discovered to have antipsychotic antipsychotic activity. Chlorpromazine helped control Chlor thought disorder, hallucinations and delusions. The The antipsychotic action of chlorpromazine had to be had accidentally discovered because because there was no basis (or paradigm) in the early 1950s for predicting the effects of chemicals on the brain and on behavior. 12 Outpatient vs. Inpatient Care Chlorpromazine was so effective that it took the place of treating schizophrenics with seemingly cruel and barbaric techniques of electroshock therapies electroshock therapies insulin shock therapy and frontal lobotomies. frontal Due Due to this drug, public mental institutions that had been used for the custodial care of schizophrenics could now be abandoned and psychotic people could lead free lives. http://www.rootsweb.com/~asylums/ Reserpine Chlorpromazine had unwanted unwanted side effects, including seizures, loss of bladder control and tardive dyskinesia (uncontrollable and purposeless facial movements) so other antipsychotic drugs ht were sought out. Reserpine from the dried root of the Indian snakeroot (Rauwolfia serpentina) had been used by Indian physicians to treat mental illness. It was “rediscovered” by the pharmaceutical companies and introduced in 1954 as another antipsychotic antipsychotic drug (Serpalan, (Serpalan, Serpasil). Serpasil). Reserpine Reserpine Depletes the Brain of Neurotransmitters Bernard “Steve” Brodie (1955) decided to “take a flier” on a quick and dirty experiment to see if there was a relationship between relationship reserpine and serotonin. He treated a dog with reserpine and found that it caused a serotonin metabolite to appear in the urine. He concluded that reserpine was an effective treatment for schizophrenia because it depleted the brain of serotonin. Arvid Carlsson found that reserpine also caused a depletion of adrenaline and noradrenaline. noradrenaline. Serotonin Is Not Involved In Schizophrenia Arvid Carlsson found that 5hydroxytryptophan, a precursor of serotonin that could pass through the blood-brain barrier and increase the serotonin levels in the brain, could not reverse the sedative effect of reserpine in mice. This indicated that the depletion of serotonin was not involved in reserpine action. Amino Acid 13 Is Noradrenaline Involved in Schizophrenia? However, L-DOPA, La precursor of noradrenaline (norepinephrine) norepinephrine) could could reverse the sedation effect of sedation effect of reserpine. reserpine. This made it seem seem likely that the depletion of noradrenaline was involved in the therapeutic effect of reserpine. reserpine. Amino Acid Noradrenaline is Not Involved in Schizophrenia The action of L-DOPA was enhanced by an inhibitor of monoamine oxidase. Monoamine oxidase causes the breakdown of monoamines, including noradrenaline. This made it seem even more likely that reserpine’s caused sedation by depleting the brain of noradrenaline. But they found that, while L-DOPA and the monoamine oxidase inhibitor reversed the effect of reserpine, the noradrenaline levels in the brain remained unchanged. Too Too Much Dopamine Is Associated with Schizophrenia and Reserpine Causes a Depletion of Dopamine As a last resort, Carlsson looked for changes in dopamine, which at that time was not thought of as a neurotransmitter but only as a precursor of noradrenaline precursor of noradrenaline. They found that dopamine did accumulate in the brains of animals treated with L-DOPA following reserpine pretreatment. Then they found that dopamine occurs naturally in the brain and reserpine is effective in fighting schizophrenia by depleting the brain of dopamine. Too Little Dopamine Is Associated with Parkinson’s Disease Reserpine treatment often induced tremors in patients tremors that were reminiscent of Parkinson’s Parkinson’s disease. Indeed it turned out that people Indeed it turned out that people who who suffer from Parkinson’s disease have too little too dopamine in their brain. Thus Parkinson’s disease is now treated by giving the patients L-DOPA, which passes Lthe blood-brain barrier and is bloodconverted into dopamine. Michael J. Fox Uses L-DOPA L- Brain Donations Dopamine Dopamine level must be balanced balanced between the high level associated with schizophrenia and the low level associated with Parkinson’s disease. The cause and cure of schizophrenia and Parkinson schizophrenia and Parkinson’s disease disease is still a mystery. Upon Upon death, hospitals ask the families to donate the brains of schizophrenics and those with other kinds of brain disorders in the hope of finding a cause and a cure. http://www.brain.northwestern.edu/pdfs/ADCC/autopsy_brochure_05.pdf http://www.brain.northwestern.edu/mdad/brainendowment.html http://images.ibsys.com/2005/0331/4334965.pdf www.michaeljfox.org 14 Guessing that a simple Parkinsonian tremor taken to its extreme would appear like no tremor at all, Dr. Oliver Sacks gave L-DOPA to his Lpatients who had been comatose with Encephalitis Encephalitis lethargica for decades as lethargica for decades as a result result of a viral infection. They They awakened!!!!! Mental Illness in the United States Disorder % of Population over 18 Mood disorders 9.5 Major depressive disorder 6.7 Mild depression depression 1.5 Bipolar disorder 2.6 Schizophrenia 1.1 Anxiety disorder 18.1 Any diagnosable mental disorder 26.2 Oliver Sacks--Botanist http://www.nimh.nih.gov/publicat/numbers.cfm#Intro Illness or Condition? Diagnostic and Statistical Manual of Mental Disorders (DSM IV) Is Complete Androgen Insensitivity Syndrome an Illness or a Condition? Is Dwarfism an Illness or a Condition? oiiaustralia.com The Finger Lakes Chapter of Little People of America held a convention at the Ramada Inn in Ithaca April 9-11. 15 Mental Diversity Is “mental illness” an illness or a condition? Mad Pride mindfreedom suitcaseexhibit nytimes John Nash: A Beautiful Mind “So at the present time I seem to be thinking rationally again in the style that is characteristic of scientists. However this is not entirely a matter of joy as if someone returned from physical disability to good physical health. One aspect of this is that rationality of aspect of this is that rationality of thought thought imposes a limit on a person's concept of his relation to the cosmos. For example, a non-Zoroastrian could nonthink of Zarathustra as simply a madman who led millions of naive followers to adopt a cult of ritual fire worship. But without his "madness" Zarathustra would necessarily have been only another of the millions or billions of human individuals who have lived and then been forgotten.” John Nash Unlike the John Nash in the movie, “A Beautiful Mind”, the real real John Nash is functioning as a mathematician and an economist without taking antipsychotic drugs. nobelprize.org-nash-interview pbs-interview Two Ways to Learn About Health and Disease: Balancing Risks and Benefits Sometimes understanding normal function helps to understand, cure and treat illness. But how But many volunteers do you get to study normal human brain function? Sometimes studying and treating mental illness Sometimes studying and treating mental illness when when we understand very little about how the brain works and about how and where a drug works helps us understand brain function. But But the patients are also part of an experiment. I will discuss two classes of drugs used to treat mental illness (monoamine oxidase inhibitors and monoamine re-uptake inhibitors). re- 16 If Neurotransmitters Are Important For Brain Function, How Are The Concentrations Of Neurotransmitters Normally Regulated? Some alleles of monoamine oxidase are associated with aggression. Monoamine Monoamine oxidases break down down dopamine, adrenaline, noradrenaline and serotonin. In general, a too high level of monoamines is correlated with aggression, a too low level is correlated with depression. Monoamine Oxidase Inhibitors (MOAIs) can Treat Depression by Increasing the Concentrations of Neurotransmitters in the Brain The concentrations of dopamine, adrenaline, noradrenaline and serotonin in the synapses of the brain can be increased by treating a person with monoamine monoamine oxidase inhibitors (MAOI). Monoamine oxidase inhibitors are used to treat depression depression and and anxiety disorders. Common MAOIs include, Emsam, Marplan, Aurorix, Nardil and Marsilid. http://www.emsam.com/ Discovery of MAOI The German WW II V-2 rocket used hydrazine for fuel. At the end of WW II, large supplies of hydrazine were available inexpensively. The explosive and toxic hydrazine was modified chemically to produce potential medicines medicines. In 1951, scientists at Hoffman-La Roche Hoffmanfound that two hydrazine compounds, isoniazid and iproniazid were isoniazid and iproniazid were effective in killing the bacterium that caused tuberculosis tuberculosis (TB). The TB patients given these hydrazine compounds danced joyfully in the danced corridors of the TB wards and it was soon realized that these drugs may be useful in treating depression. depression Discovery of MAOI While the hydrazine compounds were effective in fighting depression, they had a serious side effect in users who drank Chianti and vermouth and ate aged cheese, smoked, pickled and marinated foods and other gourmet delights that contained high levels of the non-protein amino acid tyramine. nontyramine After eating tyramine-rich foods, the hydrazine compound users tyraminedeveloped developed throbbing headaches, jaundice, high blood pressure and occasional lethal hemorrhaging. The side The side effects are caused by the fact that the hydrazine compounds inhibit the enzyme monoamine oxidase that monoamine normally breaks down tyramine the body. Indeed, the antidepressive effect of hydrazine compounds depends on their ability to inhibit MAO and the breakdown of inhibit other monoamines, including serotonin, adrenaline, noradrenaline and dopamine. TyramineTyramine-Containing Foods People taking MAOI must restrict their intake of foods high in tyramine in tyramine. 17 Receptors for Chemicals in the Synapse Solomon Snyder discovered that each neurotransmitter has a receptor receptor on the membrane of the post-synaptic neuron. postReceptors Receptors are discovered by treating tissues with low concentrations of radioactive concentrations of radioactive molecules molecules and finding the proteins that become radioactive because they bind the radioactive molecule. The affinity of the receptor must affinity match the concentration of the concentration neurotransmitter in order for postpost-synaptic potentials to be generated. Various drugs Various drugs that inhibit the re-uptake of remonoamine neurotransmitters are used in the treatment of mental illness Julius Axelrod discovered that the pre-synaptic neurons have pretransport transport proteins that take up the monoamine the monoamine neurotransmitters neurotransmitters. ReRe-uptake inhibitors increase the concentration of neurotransmitters so that their concentrations match the affinity of their receptors on the postpostsynaptic neurons. SSRIs SSRIs Are Used to Treat Mental Illness The concentrations of serotonin in the synapses can be increased by treating a person with a selective serotonin reselective reuptake inhibitors (SSRI). SSRIs are used to treat depression depression, anxiety disorders and personality disorders. Common SSRIs include, Prozac, Paxil, Zoloft, Celexa and Luvox. http://www.prozac.com/index.jsp DRIs Are Used to Treat Mental Illness The concentrations of dopamine in the synapses can be increased by treating a person with a dopamine dopamine rere-uptake inhibitors (DRI). DRIs are used to treat depression. are used to treat depression Common DRIs include, Wellbutrin and Zyban. Zyban. Cocaine causes euphoria by blocking the re-uptake of dopamine. reMethamphetamine Methamphetamine stimulates the release of dopamine and blocks its rere-uptake. http://www.wellbutrin-xl.com/ Cocaine and Methamphetamine Increase the Dopamine Concentration in Synapses Ritalin is Used to Treat ADHD Like other stimulants, Ritalin, which is prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD), causes an increase in the dopamine increase in the dopamine concentration concentration in the synapses; however, according to the manufacturer, The mode of “The therapeutic action in Attention Deficit Hyperactivity Disorder (ADHD) is not known.” http://www.drugabuse.gov/InfoFacts/ADHD.html Novartis 18 “Smart Drugs” and “Cosmetic Neurology” Even though students believe that taking “smart drugs” like Ritalin and Adderall is cheating, they feel pressured to take it to compete on exams. Should universities require urine tests on exam days in order to detect people illegally using smart drugs? Pharmaceutical advances in making smart drugs along with a greater cultural acceptance could make "cosmetic neurology of the mind” as popular as as cosmetic neurology of the body (e.g. Botox). http://www.guardian.co.uk/society/2010/feb/21/smart-drugs-students-universities www.justice.gov A Variety of Drugs Is Available to Influence the Chemical Environment of the Brain Some antidepressant drugs, including Effexor are less selective and work by inhibiting the re-uptake of serotonin, renoradrenaline and dopamine. Genes and the environment influence Genes and the environment influence the the chemicals in the brain. Presumably Presumably the various drugs modify the chemical environment in the brain to help route nervous impulses to the various regions of the brain that allow adaptive behavior in healthy environments. We do not know how. http://www.effexorxr.com/ The Placebo Effect Sharon Begley of Newsweek questioned the idea put forward by psychiatry professor Richard Friedman in Friedman in the New York Times that “there is no question that the safety safety and efficacy of antidepressants rest on solid scientific evidence.” She asked how much of the efficacy of the drug was due to the fact that a depressed person was taking a pill (the placebo effect) and how much was due to the drug itself in that pill? Fourier et al. (2010) concluded from a meta-analysis et al. (2010) concluded from meta analysis of of published reports, that “the magnitude of benefit of “the antidepressant medication compared with placebo increases with severity of depression symptoms and may be minimal or nonexistent, on average, in patients with mild or moderate symptoms. For patients with very severe depression, the benefit of medications over placebo is substantial.” www.psychiatrictimes.com jama.ama-assn.org 19 The Average vs. The Individual “Every unhappy individual is unhappy in his or her own way.” “Studies examine large group averages—not no individuals.” individuals.” “The “The meds worked for me…. But I still wonder how, and who else, these drugs may help.” www.newsweek.com Dr. Robert Klitzman Elliot Valenstein “I am convinced that biological factors may predispose some individuals toward developing a mental illness, but there is more to there biology that neurotransmitters and brain chemistry…all biological brain chemistry biological factors…depend factors…depend equally on social social and psychological variables….in their everyday practice physicians are increasingly being pressured to neglect everything but drugs and chemical explanations in treating patients with mental disorders, and therein lies a great danger.” great Are We Trained to Choose Chemicals First? Birth Control Pills vs. IUDs Are We Trained to Choose Chemicals First? Psychopharmacology of Individual People When someone has a chemical imbalance in their brain, it is in theory, possible to find a drug that will bring the unbalanced chemicals back in balance. This is not so easy because the brain is a very complicated and dynamic dynamic system. Moreover, Moreover, if the brain is the physical basis of mind, it may also be different enough for each person, that prescribing the right drugs may be an experiment in experiment itself. A supportive environment provided by friends and family can help. Processed food vs. Whole foods http://www.whatadifference.samhsa.gov/ 20 Environmental Neurology: Prozac in the Water Supply Discovering Neuropeptides in the Brain Many informational molecules have been discovered in the brain by using the following logic: If a drug like morphine, which If comes from the opium poppy, acts on the brain, there must be a receptor for it in the brain (Avram Goldstein’s Rule). If If there is a receptor for it in the brain, it is likely that there is an endogenous morphine-like morphinemolecule (Hans Kosterlitz’s Rule). Prozac is not broken down by the body and is eliminated in the urine. With 54 million people taking the drug worldwide, it has shown up in the water supply in the United Kingdom. Solomon Snyder and Candace Pert (1973) Discovered the Opiate Receptor in the Brain as a Part of Nixon’s War on Drugs The typical way to find a receptor is to grind up tissue and treat it with a radioactive molecule (e.g. morphine). The radioactive molecule will bind to Th bi the receptor with high affinity and to anything else with low affinity. So So you wash the preparation to eliminate the nonspecific binding. After washing, the receptor is identified as the protein that is still bound to the radioactive molecule. Discovery of Endorphins Hans Hans Kosterlitz and John Hughes (1975) discovered the natural euphorianatural euphoriaproducing, pain-killing opiates in the painbody. The vas deferens of the mouse is vas extremely sensitive to morphine. The vas deferens convulses in response to convulses an electric shock and morphine prevents electric morphine the convulsion. Kosterlitz and Hughes separated pig brains into different chemical fractions until they found a fraction that inhibited the electricallyelectrically-induced convulsions. The endogenous morphine like substance, end or endorphin, turned out to be an endorphin oligopeptide (a oligopeptide (a chain of 5 amino acids). 21 Endocannabinoids Just as there are opiate receptors and endorphins in the brain, there are also tetrahydrocannabinol tetrahydrocannabinol (THC) (THC) receptors for the active ingredient of marijuana. There There are also endogenous analogs of THC (anandamide and 2-AG) in the brain. Stress and the Brain Stress causes degeneration of the causes neurons in the hippocampus, a part of the limbic system of the limbic brain involved in memory memory formation. Cortisol, a catabolic steroid, catabolic mimics the effect of stress, indicating that the cortisol is the th th th stress hormone causing degeneration. Since the hippocampus is part of hippocampus is a negative feedback loop that negative inhibits the production of cortisol, a damaged hippocampus results in a chronic high level of cortisol which causes further degeneration of the neurons in the hippocampus. Chemistry of the Human Brain Monoamine neurotransmitters, including serotonin, dopamine and noradrenaline are active in the brain. Amino acids, including glycine, aspartic acid, histamine, GABA and glutamic acid function as neurotransmitters. Acetylcholine acts as a neurotransmitter in the brain. acts Stress hormones (e.g. adrenaline and cortisol), and their receptors are in the brain. Over 100 oligopeptides (e.g. endorphin), known as neuropeptides neuropeptides, exist in the human brain and probably most function as informational molecules. The sex hormones are found in the brain and there are sex receptors in the brain for them, indicating that the brain and the reproductive system are connected. The oligopeptides produced by cells of the immune immune system are found in the brain and there are receptors in the brain for them, indicating that the brain and immune system are connected. Do We Have a Second Brain? Serotonin got its name from being discovered as a chemical in the blood serum that causes ser constriction of the blood vessels that results in high blood pressure (hyper (hypertonicity). NinetyNinety-five percent of the serotonin in the body is produced by and found in the large intestine. Michael Gershon considers the nerves that innervate the intestines to be the “second brain”. Many Many Informational Molecules and Their Receptors Have Been Found in Both the Brain and the Gut. Perhaps There is Something to “Gut Feelings” and “Trusting Your Gut”. 22 Chemicals in the Brain and Personal Responsibility Just for Fun—Are any of these items Fun— moving? Or are they perfectly still? Do our chemicals make us do it? Just for Fun—Are any of these items Fun— moving? Or are they perfectly still? Just for Fun—Are any of these items Fun— moving? Or are they perfectly still? Human Beings: Who Are We? What would you do? You make the choice! Don't look for a punch line; There isn't one! Read it anyway. My question to all of you is: Would you have made the same choice? At a fundraising dinner for a school that serves learning disabled children, the father of one of the students delivered speech that would never be delivered a speech that would never be forgotten forgotten by all who attended. After extolling the school and its dedicated staff, he offered a question: "When not interfered with by outside influences, everything nature does is done with perfection. Yet my son, Shay, cannot learn things as other children do. He cannot understand things as other children do. Where is the natural order of things in my son?" The audience was stilled by the query. The The father continued. "I believe, that when a child like Shay, physically and mentally handicapped comes into the world, an opportunity to realize true human nature presents itself, and it comes, in the way other people treat that child. "Then he told the following story: Shay and his father had walked past a park where some boys Shay knew were playing baseball. Shay asked, "Do you think they'll let me play?" Shay's father knew that they'll let me play?" Shay's father knew that most most of the boys would not want someone like Shay on their team, but the father also understood that if his son were allowed to play, it would give him a much-needed sense of muchbelonging and some confidence to be accepted by others in spite of his handicaps. Shay's father approached one of the boys on the field and asked if Shay could play, not expecting much. 23 The boy looked around for guidance and said, "We're losing by six runs and the game is in the eighth inning. I guess he can be on our team and we'll try to put him in to bat in the ninth inning." Shay struggled over to the team's bench put on a team shirt with a broad smile and his father had a small tear in his eye and warmth in his heart. The boys saw the father's joy at his son being accepted. In the bottom of the eighth inning Shay's team scored few runs but was inning, Shay's team scored a few runs but was still still behind by three. In the top of the ninth inning, Shay put on a glove and played in the right field. Even though no hits came his way, he was obviously ecstatic just to be in the game and on the field, grinning from ear to ear as his father waved to him from the stands. In the bottom of the ninth inning, Shay's team scored again. Now, Now, with two outs and the bases loaded, the potential winning run was on base and Shay was scheduled to be next at bat. At this juncture, do they let Shay bat and give away their chance to win the game? Surprisingly, Shay was given the bat. Everyone knew that a hit was all but impossible 'cause Shay didn't even know how to hold the bat properly, much less connect with the ball. However, as Shay stepped up to the plate, the the pitcher, recognizing the other team putting winning aside for this moment in Shay's life, moved in a few steps to lob the ball in softly so Shay could at least be able to make contact. The first pitch came and Shay swung clumsily and missed. The pitcher again took a few steps forward to toss the ball softly towards Shay. As the pitch came in, Shay swung at the ball and hit a slow ground ball right back to the pitcher. The The game would now be over, but the pitcher picked up the soft grounder and could have easily thrown the ball to the first baseman. Shay would have been out and that would have been the end of the game. Instead, the pitcher threw the ball right over the head of the first baseman, out of reach of all team mates. Everyone from the stands and both teams started yelling, "Shay, run to first! Run to first!" Never in his life had Shay ever ran that far but made it to first had Shay ever ran that far but made it to first base. base. He scampered down the baseline, widewideeyed and startled. Everyone yelled, "Run to second, run to second!" Catching his breath, Shay awkwardly ran towards second, gleaming and struggling to make it to second base. By the time Shay rounded towards second base, the right fielder had the ball, the smallest guy on their team, who had a chance to be the hero for his team for the first time. He could have thrown the ball to the secondsecondbaseman for the tag, but he understood the pitcher's intentions and he too intentionally threw the ball high and far over the third-baseman's thirdhead. Shay ran toward third base deliriously as the runners ahead of him circled the bases toward home. All were screaming, "Shay, Shay, Shay, all the Way Shay" Shay reached third base, the opposing shortstop ran to help him and turned him in the direction of third base, and an hi th di thi shouted, shouted, "Run to third! Shay, run to third" As Shay rounded third, the boys from both teams and those watching were on their feet were screaming, "Shay, run home! Shay ran to home, stepped on the plate, and was cheered as the hero who hit the "grand slam" and won the game for his team. Human Human Beings: Who Are We? That day, said the father softly with tears now rolling down his face, the boys from both teams helped bring a piece of true love and humanity into this world. Shay didn't make it to another summer and died didn make it to another summer and died that that winter, having never forgotten being the hero and making his father so happy and coming home and seeing his mother tearfully embrace her little hero of the day! Thanks, Thanks, Robert Frost by David Ray Do you have hope for the future? someone asked Robert Frost, toward the end. Yes, and even for the past, he replied, that it will turn out to have been all right it for what it was, something we can accept, mistakes made by the selves we had to be, not able to be, perhaps, what we wished, or what looking back half the time it seems we could so easily have been, or ought... 24 Thanks, Robert Frost by David Ray The future, yes, and even for the past, that it will become something we can bear. And I too, and my children, so I hope, will recall as not too heavy the tug recall as not too heavy the tug of those albatrosses I sadly placed upon their tender necks. Hope for the past, yes, old Frost, your words provide that courage, and it brings strange peace that itself passes into past, easier to bear because you said it, rather casually, as snow went on falling in Vermont years ago. 25 ...
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