Nervous System I Lecture - Physiology CELL3210/6210 2024 PDF

Physiology CELL3210/6210 10/14/2024 18. Nervous System I Readings: Medical Physiology, Ch. 46-49 Ramon Cajal (1852-1934); the Father of Neuroscience Shared the 1906 Nobel Prize in Physiology https://www.youtube.com/watch?v=pBd7AJk1drY James Cronin, PhD...

Physiology CELL3210/6210 10/14/2024 18. Nervous System I Readings: Medical Physiology, Ch. 46-49 Ramon Cajal (1852-1934); the Father of Neuroscience Shared the 1906 Nobel Prize in Physiology https://www.youtube.com/watch?v=pBd7AJk1drY James Cronin, PhD 1911 Drawing of https://www.youtube.com/watch?v=x7k6r7AtH3Q [email protected] the hippocampus https://www.youtube.com/watch?v=QIDUKHXqtg4 Organization of the Nervous System Typical neuronal structure Golgi stains of Hippocampal Pyramidal Cells J. Neuroscience, Oct. 2005 Organization of the Nervous System Somatosensory axis of Skeletal motor nerve axis of the Nervous System the nervous system Organization of the Nervous System UCLA SOM, Class of 2022 https://www.yout ube.com/watch? v=UtHEeTzjtfM Neurons communicate to subsequent neurons via synapses; -Chemical synapses, -Electrical synapses  Electrical Synapse Gap-junction Structure Speed of transmission Membrane potential change is transmitted directly from one cell to another - bidirectional and with no delay. Sometimes it’s not fast enough Electrical Synapse Dye coupling -Made of 6 subunits around a central channel, called ‘connexon’ -Open & close randomly, with increased probability of opening under specific conditions (elevated Ca2+, depolarization,..) -Used in reflex pathways, non-neuronal cells; hapatocytes, myocardial cells, intestinal smooth muscle,… Chemical Synapse No direct contact between neuron and target; neurotransmitters are released into ‘space’ of synaptic cleft. Transmitters bind to receptors on pre & post-synaptic membrane.  Chemical Synaptic transmission 1 transmitter synthesized 7 transmitter binds to receptor molecules 2 AP arrives at presynaptic terminal 8 receptors are ligand-gated channels or 3 Depolarization opens voltage-gated Ca start signal-transduction cascade channels 9 postsynaptic current causes IPSP or 4 influx of Ca EPSP in postsynaptic cell 5 Intracellular Ca causes vesicles fusion with 10 retrieval of vesicular membrane from presynaptic membrane plasma membrane 6 transmitter is released into synaptic cleft 11 transmitter is degraded, taken back into presynaptic membrane, or both Chemical Synaptic transmission 1. synthesis: methionine sulfoximine: inhibits glutamine synthesis, experimental drug, inhibits bacteria multiplication, reduces stroke damage in models 2. Na channel blocker: Novacaine, local anesthetic 3-4-5. Vesicle fusion: Alpha Latrotoxin: from Black Widow, causes Ca2+-independent transmitter release, convulsant 6. transmitter release: tetanus toxin, blocks GABA release, convulsant Clostridium tetani Black Widow Chemical Synaptic transmission 7. receptor binding: Mirapex, binds & activates dopamine receptors, Parkinson’s treatment Diazepam (Valium)- GABA agonist, treatment for epilepsy, anxiety Clozapine- serotonin receptor agonist, antipsychotic 10. reuptake: SSRIs, antidepressants Fluoxetine (Prozac), Paroxetine (Paxil) 11. Degradation: cholinesterase inhibitors; neostigmine, Neurotransmitter Receptors Neurotransmitter Receptors can be divided into 2 classes: – Ionotropic Receptors: Large, multisubunit complexes of proteins (usually 4 or 5). Complex forms an ion channel. Fast onset, fast reversal. – Nicotinic Acetylcholine receptors, – Ionotropic Glutamate receptors (AMPA, Kainate, NMDA) – Metabotropic Receptors, or G-Protein coupled receptors (GPCRs): Single polypeptide. Activation leads to binding and activating of G proteins. Slow onset and duration. – Muscarinic Acetylcholine receptors, – Beta-adrenergic receptors.  Two Families of Postsynaptic Receptors A. Ligand-gated ion channels- transmitter binding to receptors opens ion channel allowing current flow through channel B. Metabotropic receptors- transmitter binding activates G-proteins which dissociate from receptor to interact directly with ion channel or other effector proteins (second messangers, enzymes,..) 12  G-Protein Coupled Receptors 1. Direct effect on ion channels Over half of all 2. Activation of cAMP and/or cGMP prescription drugs 3. Activation of intracellular enzymes work through 4. Activation of gene transcription http://www.youtube.com/watch?v=Glu_T6DQuLU G-protein coupled https://www.youtube.com/watch?v=ZBSo_GFN3qI receptors!  G-Protein Coupled Receptors Robert J. Lefkowitz Brian K. Kobilka The Nobel Prize in Chemistry 2012 was awarded jointly to Robert J. Lefkowitz and Brian K. Kobilka "for studies of G-protein-coupled receptors"  Post-Synaptic Effects Excitatory 1. Opening of sodium channels. 2. Depressed conduction through chloride and/or potassium channels. 3. Changes to internal cellular metabolism Inhibitory 1. Opening post-synaptic chloride channels. 2. Increase in conductance of potassium ions out of the cell. 3. Activation of receptor enzymes. Electrical Events During Neuronal Excitation The resting membrane potential: due to concentration differences and relative permeability of different ion species. Neuron at rest, Em= -65mV During EPSP, the Em is brought to -45mV During IPSP, the Em is brought to -70mV Electrical Events During Neuronal Excitation Synaptic events ‘summate’ to bring cell to threshold Spatial Summation: collective depolarization of spatially separated synapses Temporal Summation: collective summation of synaptic events occurring during their relative durations EPSPs and IPSPs are summated, or processed by the soma. Transmitters: Small-Molecule, Rapidly Acting Class I Acetylcholine Class II: The Amines Norepinephrine Epinephrine Catecholamines Dopamine Serotonin Histamine Class III: Amino Acids Gama-aminobutyric acid (GABA) Glycine Glutamate Aspartate Class IV Nitric Oxide (NO) Catecholamine Synthesis: Dopamine, Norepinephrine, & Epinephrine Phenylalanine (from diet) Phenylalaline hydroxylase L-tyrosine Tyrosine hydroxylase (TH) tyrosine hydroxylation is the limiting step in catecholamine synthesis 3,4 dihydroxyphenylanine (DOPA) L-aromatic amino acid decarboxylase (AADC) aka DOPA decarboxylase Dopamine (DA) Dopamine β-hydroxylase (DBH) DA transferred to vesicle by vesicular monoamine transporter (VMAT) where metabolized to NE Norepinephrine (NE) Phenylethanoline N-Methyltransferase (PMNT) 19 Epinephrine (Epi) Vesicular Monoamine Transporters; VMAT1-adrenal cells VMAT2- catecholamine and 5-HT neurons. VMAT2 inhibitors block catecholamine transmission. Reserpine used for treating high blood pressure and psychosis. Rauvolfia serpentina, Snakeroot Dopamine (DA) Dopamine β-hydroxylase (DBH) DA transferred to vesicle by vesicular monoamine transporter (VMAT) where metabolized to NE Norepinephrine (NE) Phenylethanoline N-Methyltransferase (PMNT) 20 Epinephrine (Epi) Inactivation of Catecholamines Selegiline 1. Diffusion videos: 2. Reuptake https://www.youtu be.com/watch?v=1 3. Enzymatic inactivation io9cBdihk0 -MAO (monoamine oxidase) https://www.yout ube.com/watch? v=Y5q1AXzd3kg MAOA - high affinity for NE & 5-HT -inhibited by clorgyline (MAO inhibitor antidepressant) MAOB -higher affinity for o-phenylethylamine -inhibited by deprenyl (Selegiline, Jumex) -antidepressant, believed to have neuroprotective effects, antiaging -Parkinson’s -Sexual dysfunction (libido) -COMT (catechol-O-mytheltransferase) COMT inhibitors used to prevent inactivation of DOPA, used in conjunction with DOPA-based Parkinson’s treatments. 21 Inactivation of Catecholamines 1. Diffusion You belong in 2. Reuptake Psychiatry: 3. Enzymatic inactivation https://www.yout ube.com/watch? -MAO (Monoamine oxidase) v=XsZJA3vvlzI -COMT (catechol-O-methyltransferase) https://www.youtub e.com/watch?v=w W8GNnI1oO4&t=1 25s Reuptake of released transmitter is major mode of inactivation. https://www.yout ube.com/watch?v -DAT (DA) dopamine transporter =Z__t-KtUDIw -NET (NE) norepinephrine transporter These are relatively poorly specific, coupled to the Na+ gradient. Cocaine increases extracellular catecholamines and 5-HT by blocking reuptake through (presumably) DAT. NET is target of tricyclic antidepressants, work primarily on NE -Elavil, Tofranil How to use Amitriptyline? (Ela vil, Endep, Vanatrip https://www.youtube.com/ ) - Doctor Explains - YouTube watch?v=FbsaX5kGbS8 https://www.yout https://www.youtube.com ube.com/watch? 22 /watch?v=3M6t2Ynm2Po v=qtq_saACxNI Serotonin Psychedelics as therapeutic agents: https://pubmed.ncbi.nl 5-Hydroxytryptamine (5-HT) m.nih.gov/36322843/ https://pubmed.nc bi.nlm.nih.gov/376 51119/ https://pubmed.ncbi. nlm.nih.gov/3700440 Tryptophan (from diet) 9/ https://pubmed.ncbi.nlm.nih.gov/36846 225/ Tryptophan hydroxylase (rate limiting) https://pubmed.ncbi.n lm.nih.gov/33125716/ https://pubmed.ncbi. 5- Hydroxytryptophan (5-HTP) nlm.nih.gov/2858522 2/ L-aromatic amino acid decarboxylase (AADC) https://pubmed.ncbi.n lm.nih.gov/32929261/ 5-HT 2 minute Neuroscience: Serotonin: https://www.youtube.com/watch?v=Xkl_x6wC0Lg 23 Serotonin, 5-Hydroxytryptamine (5-HT) Mechanisms -accumulated in vesicles by VMAT2 of SSRIs https://www.youtu be.com/watch?v= -released by exocytosis CdRoOVsa1ag -inactivated by reuptake through SERT (serotonin Pharmacology - Antidepre ssants, Animation (youtub e.com) reuptake transporter) -SSRI antidepressants; Citalopram (Celexa, Cipramil, Emocal, Sepram) Escitalopram oxalate (Lexapro, Cipralex, Esertia) Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Fluctin) Fluvoxamine maleate (Luvox, Faverin) Paroxetine (Paxil, Seroxat, Aropax, Deroxat) Sertraline (Zoloft, Lustral, Serlain) 24 Serotonin https://www.youtube.com/watch?v=twhvtzd6gXA https://www.youtube.com/watch?v=rR8rBEFulw4 5-Hydroxytryptamine (5-HT) https://www.youtube.com/watch?v=OTZvnAF7UsA& list=PL7tXl80mM4o6m8HnsmpHfJb9g9NSs4ZaX https://www.youtube.com/watch?v=S5DdektRz2I&l -accumulated in vesicles by VMAT2 ist=PL_V67p-zEfTFfSE2NNseE0FFKU1GEHNyT -released by exocytosis Drug: http://www.youtube.com/ watch?v=ffZUHWG66EA Vox: -inactivated by reuptake through SERT https://www.youtube.com/watc h?v=_5jnn1AIt7Q&t=118s -degraded by MAO https://www.youtube.com/ watch?v=XBb5v1sJhuU 25 depressivedisorder.com JAMA, The Journal of the American Medical Association January 6, 2010, Vol 303, No. 1 Context Antidepressant medications represent the best established treatment for major depressive disorder, but there is little evidence that they have a specific pharmacological effect relative to pill placebo… Study Selection Randomized placebo-controlled trials of antidepressants … included a medication vs placebo comparison for at least 6 weeks… Data from 6 studies (718 patients) were included. Results Medication vs placebo differences varied substantially as a function of baseline severity. Among patients with HDRS scores below 23, Cohen d effect sizes for the difference between medication and placebo were estimated to be less than 0.20 (a standard definition of a small effect). Estimates of the magnitude of the superiority of medication over placebo increased with increases in baseline depression severity and crossed the threshold defined by the National Institute for Clinical Excellence for a clinically significant difference at a baseline HDRS score of 25. Conclusions The magnitude of benefit of 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. Histidine (amino acid) Histidine decarboxylase Histamine -transported into vesicles by VMAT -degraded by histamine methyltransferase and MAO Hypothalamic histamine projections spread throughout the brain, mediate arousal & attention. Three types of receptors identified, all G-coupled. Antihistamines which cross BBB cause sedation (Benadryl). Antagonists also used for motion sickness due to effects on vestibular pathways. https://www.youtube.com/watch?v=EksAl7rW3cQ 27 Honest Drug Ad: https://www.youtube.com/watch?v=rbFYsYMA3No γ-aminobutyric acid (GABA) -amino acid -inhibitory neurotransmitter -derived from glucose metabolism: α-ketoglutarate (from Krebs cycle) GABA-oxoglutarate transaminase (GABA-T) (in mitochondria) glutamate Glutamic acid decarboxylase (GAD) (cystolic) GABA 28 γ-aminobutyric acid (GABA) -transported into vesicles by the ‘vesicular inhibitory amino acid transporter’, VIAAT -reuptake is primary mode of inactivation via GABA transporters (GAT) -degraded by GABA-T (GABA transaminase) 29  GABA Receptors: 3 types, GABAA,, GABAB, GABAC. The ‘A’ & ’C’ are ionotropic, ‘B’ is metabotropic. Ionotropic GABA receptor Ionotropic GABA receptors increase Cl- conductance, metabotropic receptors increase K+ conductance 30  GABA Receptors: 3 types, GABAA,, GABAB, GABAC. The ‘A’ & ’C’ are ionotropic, ‘B’ is metabotropic. Benzodiazpines: diazepam Ionotropic (Valium), GABA chlordiazepoxide receptor (Librium) – agonists, antianxiety drugs Barbituates: phenobarbital, pentobarbital – agonists, hypnotics, used for anethesia, https://www.youtube.com/watch?v=wcf1vvjPKg0 epilepsy 31 https://www.youtube.com/watch?v=DljXO8FuUKI Glutamate -excitatory amino acid -responsible for most fast excitatory neurotransmission in mammalian brain -derived from α-Ketoglutarate -transported to vesicles by VGluT -inactivated by reuptake, EAA (excitatory amino acid) transporters located on neurons and glia Are you this talented? https://www.youtube.com/watch?v=DTkiDTNV22I 32 Depiction of an excitatory amino acid (glutamate) synapse 33 Acetylcholine (Ach) Biosynthesis: Acetyl-coenzyme A choline choline acetyltransferase (Chat) (transfers acetyl group to choline) Ach -taken into vesicles by vesicular cholinergic transporter (VAChT) -inactivated extracellularly by acetylcholinesterase (AchE) into choline, which is taken into neuron by choline transporter34 Acetylcholine (ACh) synaspe 35 Cholinesterase Inhibitors http://www.th eatlantic.co m/health/arc Sarin: Chemical weapon developed by German military in late 1930s. Was hive/2013/05 /what-does-s standard chemical weapon of NATO for decades. Fatal even in very low arin-do-to-pe ople/275577/ concentrations. Used in 1980s on Kurds in northern Iraq. Used against rebels in Syrian civil war- death toll estimates exceed 1700. Malathion: Organophosphate insecticide. Widely used in US for controlling Mediterranean Fruit Fly and mosquito control. Often used to control for West Nile Virus. https://www.youtube.com/watch?v=qBk82t3KmNs Neostigmine: Drug used to improve muscle tone in myasthemia gravis pts. MG is autoimmune disease in which antibodies are formed against AchRs. https://www.youtube.com/wat ch?v=w3sJEbcT7IE https://www.youtube.com/watch?v =B-CNQ-1gyLs Municipality spraying malathion as part of a mosquito control effort. Rabbit used to check for leaks at Sarin nerve gas production plant, Rocky Mountain Arsenal, Commerce City, 36 Colorado. 20 March 1970.  February 24, 2014 Running Back From Hell https://www.run PTSD is shattering the lives of thousands of American soldiers. nersworld.com/ But some experts believe running can counter the disorder's debilitating symptoms—and help restore the joy that war erased. https://www.ncbi.nl m.nih.gov/pubmed/ ?term=exercise+an d+the+prevention+ of+depression%3A +results+of+the+H UNT+cohort+study http://www.theatlanti c.com/health/archive /2014/03/for-depress ion-prescribing-exer cise-before-medicati on/284587/ The Atlantic, March 24, 2014 For Depression, Prescribing Exercise Before Medication http://well.blogs.nyti mes.com/2011/08/ 31/prescribing-exer cise-to-treat-depres sion/?_r=0 https://www.nc bi.nlm.nih.gov/ pmc/articles/P https://www.strongstartraining.org/ MC3674785/  Summary Every step in the synthesis, packaging, release, detection (receptor binding) and degradation of neurotransmitters is a potential site for pharmacological action. https://www.youtube.com/ http://www.medicaldaily.c watch?v=-6GUdjb6WMI om/antidepressants-arent -taken-depressed-majorit y-users-have-no-disorder https://www.youtube.com/ watch?v=C7FGtYVQMFc -327940 http://www.ted.com/playlists/ 130/the_dark_side_of_data https://www.ncbi.n https://www.nimh.nih.gov/health/to lm.nih.gov/pubme pics/depression/index.shtml d/16863268 https://www.youtube.com/ watch?v=ILRqYb4ZPrk https://www.youtube.com Ketamine and Depression Review /watch?v=tOVJgYHj6kc https://pubmed.ncbi.nlm.nih.gov/36244360/ Psychedelics and Depression Review https://www.jneurosci.org/content/41/5/891.long 38