St Thomas University Precursor Substance Tyrosine Worksheet

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After studying Module 2: Lecture Materials & Resources, submit the following:

Starting with the precursor substance tyrosine, draw three diagrams showing how the various enzymes convert this substance to serotonin, dopamine and norepinephrine.

Identify and briefly describe each chemical step required to create each neurotransmitter.  

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Neurobiology and Pharmacokinetics NUR 520 P SYCHOP HARMACOLOGY Receptor: configured so that precisely shaped molecules fit and cause or prevent a response Ligand: a transmitter substance that fits and evokes a response from a receptor Neurobiological Definitions Synapse: A structure that permits a neuron to pass an electrical or chemical signal to another neuron Neurotransmission: Communication between neurons Neurotransmitters: The electrochemical messengers that send signals to from neuron to neuron. They either excite or stimulate an action in the cells (excitatory) or inhibit or stop an action (inhibitory). BRAIN FUNCTIONS FOREBRAIN MIDBRAIN HINDGRAIN The Forebrain: Functions of the Brain ◦ Controls all the higher mental functions, such as learning, speech, thought, and memory Thalamus: ◦ “Relay station;” transmits nerve impulses throughout brain Hypothalamus: ◦ Regulates bodily drives and body conditions Limbic system: ◦ Involves experiencing and expressing emotions and motivation The Midbrain: Functions of the Brain • Involved in vision and hearing, and along with the hindbrain, controls sleep, alertness, and pain • Manufactures serotonin, norepinephrine, and dopamine The Hindbrain: • Controls motor movements, heart rate, sleep, and respiration • Manufactures norepinephrine and serotonin Pharmacokinetics Absorption: getting the drug into the bloodstream Distribution: getting the drug from the bloodstream to the tissues and organs Metabolism: breaking the drug down into inactive and typically water-soluble form Excretion: getting the drug out of the body Affects 90% of all drugs, 25% of all psychotropic drugs by CYP2D6 Found primarily in the liver. Also in the intestine, lungs, brain, and kidney Definitions ➢Substrate: Enzyme surfaces that receive inducers or inhibitor enzymes ➢Inducers: Increases the drug metabolism=decrease serum drug concentration. Takes several days to weeks to develop. ➢Inhibitors: Decreases the drug metabolism=increases serum drug concentration. Happens almost immediately. CYP-450 System Smoking and CYP 450 Cigarette smoking causes the induction of CYP-450 1A2, which causes more of this enzyme to be synthesized. Maximum enzyme induction occurs with 7 to 12 cigarettes per day for some medications, such as clozapine and olanzapine. Leads to a 40% to 50% reduction in serum level. If a patient smokes half of a pack or more, a higher dose of medication is needed. Same effects occur from secondhand smoke. The CYP1A2 Enzyme ❖Amitriptyline ❖Propranolol ❖Theophylline ❖Olanzapine ❖Naproxen ❖Nortriptyline ❖Acetaminophen ❖Desipramine ❖ Carbamazepine ❖ Cigarette smoking (PAH) ❖ Charbroiled Food ❖ Echinacea ❖Clozapine ❖Fluvoxamine ❖Coumadin ❖Haloperidol ❖ Mirtazapine ❖Imipramine ❖ Phenobarbital ❖ St. John’s Wort ❖ Broccoli ❖ Cabbage ❖ Phenytoin ❖ Insulin ❖ Cauliflower Retrieved from : https://apotential.wordpress.com/ 2011/08/22/how-to-memorize-cyp450/ Normal metabolizers: persons with one or two functioning copies of CYP2D6 or CYP2C19 Metabolism and Genetics Ultra-rapid metabolizers: multiple copies of CYP2D6 or CYPC19. High risk for poor efficacy. About 10% to 29% of people who are of East African or Middle Eastern descent are ultra-rapid metabolizers of CYP2D6 drugs Poor metabolizers: Patients with two inactivated copies of either CYP2D6 or CYPC19. High risk for toxicity. About 5% to 10% Caucasians higher likelihood to have lower CYP2D6 activity, making them poor metabolizers of CYP2D6 drugs Metabolism: Genetic Considerations Some Examples: Cardiovascular effects of propranolol ◦ Asian descent - more sensitive ◦ African descent - less sensitive Caucasians ◦ 5-10 % of Caucasians are poor metabolizers of CYP 2D6 Asian descent ◦ 20% people of Asian descent have educed activity CYP 2C19 ◦ May require lower doses of certain psychotropics Block metabolism: TCAs and drugs for Alzheimer’s disease Block reuptake: SSRI and other antidepressants Block receptors: antagonists Psychotropics, Drugs and Neurotransmitters Stimulate or block auto-receptors Stimulate receptors (agonists) Stimulate receptor affinity (Benzodiazepines) Stimulate release of neurotransmitter (Amphetamines stimulate release of dopamine) High concentration in brain Point-to-point communication Amino Acid Neurotransmitters Consistently excitatory or inhibitory Fast acting, short duration Glutamate Aspartate GABA Glycine Glutamate ➢Principal excitatory NT ➢Biosynthesized as byproduct of cell metabolism ➢Removed by reuptake Major receptor types ◦ NMDA ◦ AMPA ◦ Kainate ➢ At high levels, can have major neurotoxic effects. ➢ Implicated in the brain damage caused by stroke, hypoglycemia, sustained hypoxia or ischemia, and some degenerative diseases such as Huntington’s or Alzheimer’s. Gamma Aminobutyric Acid (GABA) ➢ Principal Inhibitory NT ➢ Biosynthesis: Glu Glutamic Acid Decarboxylase (GAD) and B6 • Agonists Benzodiazepines Barbiturates Ethyl alcohol (EToH) GABA ➢ Found in the brain. ➢ Modulate other neurotransmitter systems rather than to provide a direct stimulus. ➢ Prevents brain from overstimulation ➢ Reduction in GABA results in epilepsy GABAa Binding Sites Benzodiazepine (Agonist) ◦ Probably also site for alcohol Barbiturate (indirect agonist) Steroid (indirect agonist) Picrotoxin (inverse agonist) Kandel, 2013 Biogenic Amines Medium concentration in brain Modulatory functions ◦ Excitatory or inhibitory as a function of receptor Slow acting, long duration Examples: ◦Acetylcholine ◦Epinephrine ◦Norepinephrine ◦Dopamine ◦Serotonin The role of histamine in mental illness is under investigation. Histamine It is involved in peripheral allergic responses, control of gastric secretions, cardiac stimulation and alertness. Some psychotropic drugs block histamine, resulting in weight gain, sedation, and hypotension. Acetylcholine (ACh) Mostly excitatory effects Removal Synthesis Acetyl CoA + Choline CoA + Choline Acetyltransferase ACh (ChAT) ACh Acetylcholine Esterase (AChE) Acetate + Choline • Synthesized from dietary choline found in red meat and vegetables • 2 receptor types • Nicotinic • Muscarinic Major ACh Pathways Dorsolateral Pons → mid/hindbrain [REM sleep] Basal Forebrain → cortex [Learning (esp. perceptual), Attention] Medial Septum → Hippocampus [Memory] ➢ Found in the brain, spinal cord, and peripheral nervous system ➢ Involved in sleep/wake cycle and muscle stimulation. ➢ Alzheimer’s disease= decreased acetylcholine-secreting neurons ➢ Myasthenia gravis=reduced acetylcholine receptors Major ACh Pathways (Kandel, 2013) Monoamines Catecholamines Indolamines Dopamine- DA ◦ Dopaminergic Serotonin- 5-HT ◦ Serotonergic Norepinephrine- NE ◦ Noradrenergic Epinephrine- E ◦ Adrenergic Dopamine Rewarding/motivating effects Biosynthesis: Tyrosine L-DOPA Tyrosine Hydroxylase DA DOPA Decarboxylase • Dopamine reuptake transporter (DAT) • 5 receptor types Dopamine (DA) ➢ Located primarily in the brain stem ➢ Involved in the control of complex movements, motivation, cognition, and regulation of emotional responses. ➢ Dopamine is generally excitatory and is synthesized from tyrosine, a dietary amino acid. ➢ Implicated in schizophrenia, other psychoses, movement disorders like Parkinson’s disease. ↑Dopamine Schizophrenia D1=Nigrostriatal (Substantia Nigra → Striatum) [Motor movement] D2=Mesolimbic (VTA → limbic system) [Reinforcement and Addiction] D3=Mesocortical (VTA → prefrontal cortex) [Working memory and planning] D4=Tuberoinfundibular tract (hypothalamus → pituitary) [neuroendocrine regulation] Major DA Pathways Major DA Pathways Kandel, 2013 Norepinephrine (NE) Generally excitatory behavioral effects Biosynthesis: DA NE Dopamine Beta-hydroxylase • Many receptor types Ø Norepinephrine (noradrenalin), the most prevalent neurotransmitter in the nervous system Ø Precursor to Epinephrine (adrenaline) has limited distribution in the brain but controls the fight-or-flight response in the peripheral nervous system Ø Involved in pulse, blood pressure, changes in attention, learning and memory, sleep and wakefulness, and mood regulation. Ø Excess norepinephrine: several anxiety disorders Ø Deficits: memory loss, social withdrawal, and depression Norepinephrine Major NE Pathway Locus Ceruleus → throughout brain [vigilance and attentiveness] Primarily located in the brain stem Kandel, 2013 Serotonin Varying excitatory and primarily inhibitory behavioral effects Biosynthesis: Tryptophan 5-HTP 5-HT Tryptophan Hydroxylase 5-HT Decarboxylase • At least 14 receptor types, all metabotropic and postsynaptic except: • 5-HT1A,B,D (autoreceptors) – found in CNS • 5-HT3 (inhibitory, ionotropic) – found in the intestines Major 5-HT Pathways Dorsal Raphe Nuclei → cortex, striatum Medial Raphe Nuclei → cortex, hippocampus ➢ Produced in the brain and intestines ➢ Serotonin contributes to the delusions, hallucinations, and withdrawn behavior seen in schizophrenia. ➢ Some antidepressants block serotonin reuptake causing longer availability of 5-HT in the synapse= improved mood. 5-HT Roles: Mood regulation Eating disorders Sleep and dreaming Arousal Sexual behavior Pain Aggression Indirect Monoamine Agonists MAOIs Reuptake blockers (SSRIs) ◦ Tricyclic antidepressants ◦ Imipramine ◦ Desipramine ◦ Cocaine & Amphetamine Opioids Receptors-Neuropeptide Receptor High affinity ligands mu -endorphin, enkephalins (primarily analgesic) delta enkephalins (some analgesia) kappa dynorphins (negative side effects) • Opioids act at all opioid receptors, but with different affinities • Distributed throughout brain and spinal cord, especially in limbic areas • Morphine and heroin are agonists that bind to receptor sites, thereby increasing endorphin activity • Some overlap but quite distinct localizations • Co-localized with other transmitters • Modulatory functions, mostly inhibitory Muscarinic Blockage Possible Effects of Receptor Binding • Blurred Vision • Dry mouth • Constipation • Urinary difficulty Alpha 1 Antagonism • Orthostatic hypotension • Ejaculatory failure Antidepressants: Possible effects of receptor binding (Varcarolis, 2011) Neurotransmitters and Related Disorders Neurotransmitter Mental Disorder ↑Dopamine Schizophrenia ↓ Dopamine Parkinson’s Disease ↓Norepinephrine Depression ↓Serotonin Depression ↓Acetylcholine Alzheimer’s disease ↓ GABA Anxiety ↑Glutamate Excitotoxicity leading to neuronal death, migraine ↓Glutamate Concentration, mental exhaustion References Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine. Accessed July 23, 2019, via the Web: http://medicine.iupui.edu/flockhart/table.htm. Halter, M. & Varcarolis, E. (2014). Varcarolis' foundations of psychiatric mental health nursing : a clinical approach. St. Louis, Mo: Elsevier. Kandel, E. (2013). Principles of neural science. New York: McGraw-Hill. Stahl, S. M., & Muntner, N. (2017). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). Cambridge: Cambridge University Press.
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Introduction
Tyrosine is a hydrophilic amino acid that forms multiple proteins and aids the creation
of several hormones (Salamanca et al., 2020). This paper focuses on how various enzymes
change tyrosine to serotonin, dopamine, and norepinephrine. Serotonin is a chemical that aids
neuronal communication in the CNS and throughout the body. Second, dopamine is also a
neurotransmitter and a chemical precursor to other substances l...


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