PNS Efferents: Autonomic Nervous System PDF

PNS Efferents: Autonomic Nervous System October 15, 2024 instructional materials ©Kim Nixon, 2020 Lecture 29- 1  Objectives: PNS Efferents - Autonomic Nervous System 1. Describe the basic functional and structural organization of the autonomic nervous syst...

PNS Efferents: Autonomic Nervous System October 15, 2024 instructional materials ©Kim Nixon, 2020 Lecture 29- 1  Objectives: PNS Efferents - Autonomic Nervous System 1. Describe the basic functional and structural organization of the autonomic nervous system. 2. Differentiate sympathetic versus parasympathetic anatomy, outflow and neurotransmitters. 3. Understand basic neurotransmission for the ANS and be able to differentiate neurotransmission in the parasympathetic versus sympathetic divisions. 4. Define autonomic nervous system effects on specific effector organs. Differentiate parasympathetic versus sympathetic effects. 5. Understand the idea of an autonomic reflex and what functions utilize a reflex 6. What are CNS control centers for the ANS? Resources: Chapter 7 in Sherwood. Lecture 29- 2 REMINDER: Major Divisions of the Nervous System CNS = Brain & Spinal Cord PNS = everything else Sherwood Fig 5-1 Lecture 29- 3 Sensory & Motor aspect of ANS “Interoreceptors” 📷:Christine L. Miller, Thompson Rivers University🇨🇦 Lecture 29- 4  Contrast Somatic Motor & Visceral (ANS) Motor Somatic 1 motor neuron: cell body in Spinal cord innervates effector muscle. Autonomic (visceral) 2 motor neurons in series: 1st neuron cell body is in spinal cord (preganglionic) 2nd neuron cell body is in autonomic ganglion (postganglionic) innervates effector Lecture 29- 5  ANS pathways: a 2 neuron chain Autonomic nerve pathways consist of a 2-neuron chain – Preganglionic neuron: synapses with the cell body of the postganglionic fiber in a ganglion outside the CNS – Postganglionic neuron: sends axons that end on the effector organ Central nervous system / Autonomic ganglion Effector organ Spinal Cord Preganglionic Postganglionic fiber fiber CNS Preganglionic influence neurotransmitter Postganglionic neurotransmitter Sherwood Fig 7-1 Lecture 29- 6  Autonomic nervous system Two subdivisions: Parasympathetic system - dominates in quiet, relaxed “rest-and-digest” situations. - Body-maintenance activities such as digestion - “Cranial sacral” Sympathetic system - dominates in emergency or stressful “fight-or-flight” situations. - Responses that prepare body for strenuous physical activity - “Thoracolumbar” Two neuron chain: CNS→autonomic ganglion→effector organ Nearly all organs receive dual innervation by PsNS and SNS Operates by visceral reflexes Lecture 29- 7 ANS: dual innervation Sympathetic Parasympathetic Sherwood Fig 7-3 Lecture 29- 8  Parasympathetic Nervous System Anatomy: “Cranial-Sacral” Outflow Preganglionic parasympathetic neurons: Cranial nerve nuclei III, VII, IX, X - Oculomotor Nerve (III) - ciliary muscles, pupillary sphincter muscle of the eye - Facial Nerve (VII) - submandibular and sublingual salivary, lacrimal, & nasal glands - Glossopharyngeal Nerve (IX) – parotid glands - Vagus Nerve (X) - Carries 75% of preganglionic parasympathetic axons. Parasympathetic innervation to thoracic & abdominal region Sacral spinal cord (S2 – S4) - Project via the pelvic nerves to pelvic ganglia located in bladder, ureters, descending colon, rectum, and reproductive organs Guyton 60-3 Postganglionic neurons in a ganglia near or within the walls of the effector organ Majority pass uninterrupted, directly to target organ. Specific innervation Lecture 29- 9  Parasympathetic Responses “Rest and digest” SLUDD: Organ Action - Salivation Pupil Constriction - Lacrimation Eye Lens Accommodation - Urination Lacrimal Gland Secretion - Digestion Salivary Gland Secretion - Defecation Secretion, Peristalsis, Gastrointestinal Tract 3 Decreases: Sphincter relaxation - heart rate Heart Decrease heart rate - airway diameter Detrusor Contraction - pupil diameter Bladder Internal sphincter relaxation Bronchi/Bronchioles constriction Lecture 29-10  Anatomy of Sympathetic Nervous System “Thoracolumbar” output Sympathetic Chain Ganglia Preganglionic neurons bilateral, in spinal segments T-1 to L-2. Splanchnic nerves to celiac, hypogastric Postganglionic neurons Sympathetic chain ganglia: - Innervates smooth muscle of blood vessels and piloerector muscles, sweat glands - Innervate cardiac muscle, smooth muscle of bronchi and iris - ~8% of nerve fibers within spinal nerves Prevertebral ganglia – Celiac ganglion – Hypogastric plexus Adrenal medulla….. (next slide) Lecture 29-11  Importance of Adrenal Medulla E and NE almost always released by adrenal medulla at same time that different organs stimulated by generalized sympathetic activation Capability of E and NE to stimulate structures of the body that are not innervated by direct sympathetic fibers – About 20% of hormone release is norepinephrine – About 80% of hormone release is epinephrine (adrenaline) Chromaffin cells synthesize epinephrine Lecture 29-12  Sympathetic Responses Organ Action Eye Dilation Increased heart rate Heart “Fight or Flight” Increased Contractility Salivary Glands Viscous Secretion Bronchi/Bronchioles Relaxation Sweat Glands Secretion Vascular Smooth Contraction Muscle Relaxation Inhibits Secretion GI Tract Inhibits Motility Sphincter Contraction Relax Detrusor Muscle Bladder Contract Internal Sphincter Lecture 29-13  Mass Discharge of the Sympathetic Nervous System Sympathetic nervous system can discharge simultaneously as a complete unit (mass discharge) Usually initiated by the hypothalamus in response to fear, severe pain, or rage Change in response Physiological Parameter to Mass Discharge Arterial Pressure Blood Flow skin, viscera; cardiac & skeletal muscle Cellular Metabolism Blood Glucose Concentration Muscle and Liver Glycolysis Muscle Strength Mental Activity Blood Coagulation Diameter of Respiratory Airways Lecture 29-14  Autonomic Neurotransmitters some cardiac muscle cardiac muscle 1. All preganglionic fibers = acetylcholine 2. postganlionic fibers of para = acetylcholine 3. postganglionic of symp = most are adrenergic; few are ACh modified from Costanzo LS, Physiology 2nd ed., Figure 2-1. Lecture 29-15 Adrenergic Neurotransmission Ligand = epinephrine (adrenaline) or norepinephrine May be excitatory or inhibitory depending on effector These receptors can respond to ANS (neurotransmitter) or to adrenaline released from the adrenal medulla (hormone) Most sympathetic postganglionic cells - effectors innervated by sympathetic division Sympathetic stimulations tend to be more widespread Sympathetic reactions tend to be longer lasting because transmitter substance is not directly broken down but diffuses away (COMT/MAO take longer to inactivate) Lecture 29-16  Adrenergic Receptors (all GPCRs) Ligand = Norepinephrine or Epinephrine (adrenaline) - NE can be released as neurotransmitter or hormone - E released as hormone May be excitatory or inhibitory depending on receptor and system Receptors…. a receptors: ß receptors: a1: generally excitatory ß1: generally excitatory a2: generally inhibitory ß2: generally inhibitory ß3: only found on cells of brown adipose tissue (thermogenesis) Activity terminated in 1 or 2 ways: – Reuptake by neuron that released it – Enzymatically inactivated: Catechol-O-methyltransferase (COMT) Monoamine oxidase (MAO) Lecture 29-17  Summary of Sympathetic Functions Organ Action Receptor Eye Dilation α1 Do not have to Increased heart rate β1 memorize Heart Increased Contractility β1 adrenergic receptors for this Salivary Glands Viscous Secretion β1 lecture. But you will Bronchi/Bronchioles Relaxation β2 need in future! Sweat Glands Secretion mAch ß know sweat glands! Vascular Smooth Contraction α1 Muscle Relaxation β2 Inhibits Secretion α2 GI Tract Inhibits Motility β2 Sphincter Contraction α1 Relax Detrusor Muscle β2 Bladder Contract Internal α1 Sphincter Lecture 29-18  Autonomic Reflexes ANS maintains visceral homeostasis through autonomic reflexes Reflex Arc! Receptor Sensory neuron Integrating center Sympathetic chain ganglion Motor neurons Effector Fig. 14.7 Marieb & Hoehn, 2010, Human Anatomy and Physiology, 8thed Lecture 29-19  FYI: Body Functions Regulated by Autonomic Reflexes Blood Pressure (see next slide for example) Salivation Gastric secretions Defecation Gallbladder emptying Pancreatic secretions Micturition (urination) Sweating Blood glucose concentrations Lecture 29-20  Autonomic Control of Blood Pressure: Baroreceptor Reflex Lecture 29- 21 Autonomic control by higher centers Cerebrum/limbic system Thoughts/emotions can influence ANS function via hypothalamus. Hypothalamus ANS integration ctr nuclei monitor BP, body temp, feeding, digestion, etc. directly initiates autonomic responses through direct projections onto preganglionic neurons regulates autonomic responses through projections to autonomic centers in the brain stem Brain stem ANS reflex center Spinal cord ANS reflex center - urination, defecation, reproductive behaviors Lecture 29-22 Summary: Parasympathetic vs Sympathetic Parasympathetic Sympathetic Oversimplified function “Rest and digest” “Fight or Flight” Neurotransmitter ACh ACh, EPI, NE Preganglionic neuron Craniosacral Thoracolumbar Location of ganglia Close to the organ Close to the cord Preganglionic neuron Long Short Postganglionic neuron Short Long Connectivity Specific Ramified Regulation of end organs Independent Coordinated Essential for life?? Yes No Lecture 29-23 Lecture 29- 24 Sherwood Table 7-2 Lecture 29-25  Great summary slide of important distinctions between Sympathetic and Parasympathetic N.S. Sherwood Table 7-3 26 Lecture 29- PNS Efferents: Motor Control October 15 - 17, 2024 Instructional materials ©Kim Nixon, Ph.D., 2020 Lecture 30-31 1  Objectives- PNS Efferents: Motor Control 1. Define and differentiate the 3 types of movement. 2. Know the 4 major CNS regions involved in integration of motor function. 3. Differentiate the roles of CNS regions involved in voluntary movement: motor cortices - where is the motor plan formed, translated or executed? Understand the basic anatomy and role of the cerebellum to motor control. Differentiate the neuroanatomy and contributions of the Basal Ganglia to motor control, (to be presented in detail with Parkinson’s Disease). Define the corticospinal tract and differentiate from DCML, ALST tracts 4. Be able to identify symptoms of damage to the 3 motor brain regions 5. Understand spinal cord anatomy for motor function. 6. Know muscle essentials for motor control. 7. Differentiate the muscle sensory receptors structure and function (what each one senses) connections to the spinal cord and/or CNS role in reflexes 6. Have a general knowledge of the 3 reflexes circuits presented, and especially the role of each in movement. Lecture 30-31 2  Types of Movements Voluntary (cortex, cerebellum, basal ganglia) Involuntary (spinal cord; reflexes) Rhythmic motor patterns (spinal cord; brain stem) Lecture 30-31 3 REMINDER: Major Divisions of the Nervous System CNS = Brain & Spinal Cord PNS = everything else This Thursday Sherwood Fig 5-1 Lecture 30-31 4  Brain - Gross Neuroanatomy 3 vesicle 5 vesicle Major derivatives stage stage Forebrain Telencephalon Cerebral cortex Basal ganglia Limbic system Olfactory bulbs Diencephalon Thalamus Hypothalamus Midbrain Mesencephalon Substantia Nigra Tegmentum Red Nucleus Reticular formation Tectum (colliculi) Hindbrain Metencephalon Pons Cerebellum Myencephalon Medulla Lecture 30-31 5 Regions of the Brain in Voluntary Movement Premotor Primary 3 Major Regions: cortex motor Somatosensory cortex cortex Cerebral Cortex Basal Ganglia Basal Cerebellum ganglia Thalamus Smaller Roles: Cerebellum Red Nucleus Reticular formation Brain stem Pons Spinal cord Thalamus Sherwood Table 8-3 Lecture 30-31 6 Motor Control - Cortex somatosensory Premotor Ctx Supplemental Motor Ctx Lecture 30-31 7 Cortical Control of Voluntary Movement 1. Premotor Cortex - mental planning and “staging” of movement - anterior forms motor image, posterior translates it 2. Supplemental Motor Cortex - integrates movement - bilateral movements - “background movements” 3. Primary motor cortex - execution of movements Guyton, Fig 55-1 Lecture 30-31 8 Motor Homunculus… Motor Lecture 30-31 9 Compare: Motor and Sensory… Motor Sensory Lecture 30-31 10 Specialized Motor Regions in Cortex Edited Guyton 55-3 Lecture 30-31 11 Voluntary Movement: Information Flow Sensation è Movement 1. Sensory Ctx (detect it) 2. Sensory Assoc Ctx 5 (integrate it) 2 4 3. Prefrontal Ctx (think about it/plan) 3 4. Premotor/Suppl Ctx 1 (image/translate it) 5. Primary Motor Ctx** (tell SC to do it) 6. Spinal cord 6.To Spinal cord = (do it!) contract muscle & Move! Lecture 30-31 12  Outgoing Pathways from Motor Cortex TO Spinal Cord - Direct - Corticospinal Tract - Indirect – Red Nucleus - Reticular Formation TO Other Cortical regions TO Basal Ganglia Direct - Corticospinal = blue Indirect = Red Lecture 30-31 13  Corticospinal Tract aka “Pyramidal tract” or “upper motor neurons” controls speed and precision Efferent path! of fine motor Most fibers cross (medulla) and synapse on interneurons in the spinal cord. Betz cells – 16µm giant pyramidal cells Lecture 30-31 14 Red Nucleus: alternative tract to Spinal Cord 1. “Accessory route” 2. Rough topographical map 3. Closely associated with cerebellar function (comparator function) 4. Control of distal motor groups, upper limbs Lecture 30-31 15 Symptoms of Cortical Damage Positive Signs 1. Spasticity 2. Exaggerated spinal reflexes 3. Babinski response Negative Signs 1. Hypotonia 2. Loss of sensation (damage to sensory cortex) 3. Apraxia 4. Aphasia Lecture 30-31 16 Ques%ons on cortex? Lecture 30-31 Regions of the Brain in Voluntary Movement Premotor Primary 3 Major Regions: cortex motor Somatosensory cortex cortex Cerebral Cortex Basal Ganglia Basal Cerebellum ganglia Thalamus 5 nuclei of the basal ganglia: Cerebellum caudate “striatum” putamen globus pallidus Brain stem substantia nigra Spinal cord subthalamic nucleus Sherwood Table 8-3 Lecture 30-31 18 Basal Ganglia: Direct vs. indirect pathway D1 Glutamate D2 GABA é movement Dopamine D1 D2 Take home message: Direct pathway: enables movement Indirect pathway: inhibits movement Lecture 30-31 19  Cerebellum Compares actual with intended mvmt “Timing & coordination of movement; Spinocerebellum comparator” Cerebrocerebellum Sherwood Fig 5-18 Vestibulocerebellum Lecture 30-31 20 Cerebellar Comparator Function 1. Motor Ctx è SC “Intent” 3. Lower motor neurons (SC) è Muscles = movement! Thalamus 4. Muscle proprioception “actual mvmt” è CB “Intended” Motor Planèè CB 2. Motor Ctx collateral axon è CB (tells CB intended motor plan) ⬅⬅‍ Tweaks 5. Intended & Actual info meet at CB; are compared. 5.è6. CB tweaks intent (at SC via red nucleus) “Actual” è è “Actual” è è 5.è7. CB è Motor Ctx (CB informs Motor Ctx via thalamus what it did, so cortex can improve next time) Lecture 30-31 21 Damage to Cerebellum Ataxia Past Pointing Intention tremors Hypotonia “Failures of progression” Lecture 30-31 22 Ques%ons Basal Ganglia? Cerebellum? Lecture 30-31 23  Types of Movements Voluntary (cortex, cerebellum, basal ganglia) Involuntary (spinal cord; reflexes) Rhythmic motor patterns (spinal cord; brain stem) Lecture 30-31 24 Spinal Cord Anatomy for Motor Control Ventral Horn = Motor Fundamentals: 1. Dermatomes 2. White v. Grey Matter 3. Neurons of the SC Lecture 30-31 25 Spinal Segments = Dermatomes y o to m e s M Cervical (C1-C8) Head, neck, shoulders, parts of upper arms and hands Thoracic (T1-T12) Arms, hands, and trunk Lumbar (L1-L5) Waist, thighs, legs, and part of feet Sacral (S1-S5) Back of legs, buttocks, anus Sacrococcygeal Lecture 30-31 26 Spinal Cord Anatomy for Motor 1. Dermatomes ✔ 2. White v. grey matter white = tracts grey = unmyelinated neurons grey = cell bodies of neurons (interneurons, motor neurons) 3. Types of cells Lecture 30-31 27 Spinal Cord Anatomy for Motor 1. Dermatomes ✔ 2. White v. grey matter ✔ 3. Types of cells Interneurons Motor neurons - Alpha motor neurons (A𝝰) - Gamma motor neurons (A𝛾) Interconnec(ons between motor neurons and interneurons are responsible for most of the integra(ve func(ons of the spinal cord. Lecture 30-31 28  Review on own: Skeletal Muscle Basics for Motor Control Flexion Extension Origin Origin of biceps of triceps Biceps Triceps contracts contracts Insertion Insertion of biceps of triceps Tendons vs. ligaments Antagonistic muscle pairs: - Flexion = Contract a flexor muscle, closes joint angle (e.g. biceps) - Extension = Contract an extensor muscle,opens joint angle (e.g. triceps) Lecture 30-31 29  Skeletal Muscle Basics for Motor Control From CNS Alpha motor neuron axon Extrafusal (“ordinary”) muscle fibers Capsule To CNS Intrafusal (spindle) muscle fibers Gamma motor neuron axon Sensory Afferent Contractile end portions of intrafusal fiber neuron axons Noncontractile central portion of annulospiral intrafusal fiber endings flower-spray endings (a) Muscle spindle Skeletal muscle (extrafusal fiber) Afferent fiber Golgi Tendon Organ Collagen Tendon Fundamentals: Extrafusal vs Intrafusal Fibers Bone Alpha Motor Neuron vs Gamma Motor Neuron Muscle Spindle vs. Golgi Tendon Organ (b) Golgi tendon organ Edited from Sherwood Fig 8-23 Lecture 30-31 30 Two types of motor neurons 1. Alpha Motor Neurons (Aa) large (14 µm) branches to innervate extrafusal muscle fibers a motor neuron + extrafusal fibers = Motor Unit excites CONTRACTION of skeletal muscle fibers 2. Gamma Motor Neurons (Ag) smaller (5 µm) and half as many innervates intrafusal muscle fibers Controls muscle tone Lecture 30-31 31  Muscle Spindles = Sensory Receptors (proprioception!) Alpha motor neuron axon Extrafusal fibers Built around 3 - 12 intrafusal muscle fibers. Sensory Afferent Innervated by Gamma motor neuron axons neurons. Intrafusal Attached to the extrafusal (spindle) muscle fiber at each end. muscle fibers Gamma Central portion has no actin motor Contractile end portions or myosin (\ no contraction) neuron and acts as the sensory of intrafusal axon fiber receptor. Afferent is A𝝰 – fastest in body Edited from Sherwood Fig 8-23; 8-24 Lecture 30-31 32 Golgi Tendon Organ = Sensory Receptor (proprioception!) Encapsulated at the end of muscle fibers as they attach to tendon Skeletal muscle 10-15 extrafusal muscle (extrafusal fiber) fibers per single GTO Detects muscle TENSION Afferent ”sensory” fiber Golgi Tendon Organ Via A𝝰 fibers=fastest Collagen Synapse on interneuron Tendon Bone Edited from Sherwood Fig 8-23 Lecture 30-31 33 Remember…. 3. Nerve Fibers that Transmit Signal A fibers: CV 6 - 120 m/sec (muscle spindles, tactile) A𝝰 - 70 -120 m/sec (fastest) Ab - 35 - 85 m/sec Ag - 10 - 50 m/sec Ad - 6 - 30 m/sec C fibers: CV 0.5 - 2.0 m/sec (most temperature, aching pain, tickle, crude touch/pressure) Modified from Guyton 46-6 Lecture 30-31 34 Motor Function of the Spinal Cord = Reflexes Stretch reflex (monosynaptic) Flexor Withdrawal reflex Crossed Extensor reflex Golgi Tendon reflex Posture/Locomotion not covered Scratch Autonomic ✔ Lecture 30-31 35  Motor Control in Spinal Cord: Spinal Reflexes Reflex Arc Typical reflex arc: 1) sensory neuron = detects stimulus 2) Interneurons – (most often) can be excitatory or inhibitory 3) Motor neurons = muscle contraction Lecture 30-31 36  Motor Control in Spinal Cord: Spinal Reflexes Reflex Arc Typical reflex arc: 1) sensory neuron = detects stimulus 2) Interneurons – (most often) can be excitatory or inhibitory 3) Motor neurons = muscle contraction Lecture 30-31 37  Muscle Spindles = Sensory Receptors Alpha motor a. Monosynaptic Stretch Reflex neuron axon Extrafusal fibers Descending “efferents” coactivate alpha and gamma motor neurons Sensory Afferent neuron axons Extrafusal Intrafusal (spindle) fiber muscle fibers Muscle Spindle Afferent SC Gamma Contractile motor Gamma motor neuron end portions neuron Intrafusal of intrafusal axon fiber fiber Alpha motor neuron Edited from Sherwood Fig 8-23; 8-24 Lecture 30-31 38  Muscle Stretch Reflex Extensor muscle of knee (quadriceps femoris) Muscle spindle Patellar tendon KEY Alpha motor = Synapse neuron Sherwood Fig 8-25 Lecture 30-31 39 Muscle Stretch Reflex…But in reality part I (in reality, two additional circuits contribute to finely tuned kick) Stretch reflex circuit (in isolation) Reciprocal inhibition circuit Lecture 30-31 40 Muscle Stretch Reflex …but in reality part II α motor neuron α motor neuron (Muscle stretch) α motor neuron Lateral Inhibition circuit - focuses the signal. Lecture 30-31 41 Flexor Withdrawal Reflex a. Excitatory interneuron stimulates motor neuron to contract biceps b. Inhibitory interneuron inhibit opposing muscle pair, the triceps c. Divergent interneuron sends info to the brain. Lecture 30-31 42 Crossed Extensor Reflex Compensation of the opposite limb to the flexor withdrawal reflex interneurons cross to the contralateral gray matter and activate extensors and inhibit flexors (by reciprocal inhibition) delayed effect - which highlights the role of many interneurons Lecture 30-31 43 Golgi Tendon Function = Golgi Tendon Reflex Entirely inhibitory Function: - Lengthening reaction = protective Seeley A&P Fig 12.7 - Equalizes contractile force Lecture 30-31 44 Skeletal Muscle Physiology October 17, 2024 Adobe Stock Instructional materials ©Kim Nixon, Ph.D., 2020 Lecture 32- 1  Objectives-Skeletal Muscle Physiology 1. Differentiate skeletal muscle from cardiac and smooth. 2. Understand the key elements of the neuromuscular junction and how they drive muscle contraction. 3. Know muscle anatomy necessary for muscle contraction. 4. Differentiate roles of myosin and actin (thick and thin filaments) 5. What is meant by sliding filament mechanism, cross bridge activity, and power stroke? 6. Understand excitation contraction coupling and the role of the role of Ca2+ and ATP in this process. Resources: Sherwood Chapter 7 (NMJ), 8 Lecture 32- 2 REMINDER: Major Divisions of the Nervous System CNS = Brain & Spinal Cord PNS = everything else TODAY! Sherwood Fig 5-1 Lecture 32- 3  Review on own: Types of Muscle 1) Skeletal 2) Cardiac 3) Smooth Multiple nuclei in Intercalated disc Smooth muscle cell single cell Cell nucleus Cell nucleus Skeletal muscle cell (muscle fiber) Cardiac muscle cell (Cells separated for clarity) Striated muscle, voluntary Striated muscle, involuntary Unstriated muscle, involuntary Bundles of long, thick, Interlinked net- work of short, Loose network of short, slender, cylindrical, striated, contractile, slender, cylindri- cal, striated, spindle-shaped, unstriated, multinucleated cells that extend branched, contrac- tile cells contractile cells. Arranged in the length of the muscle connected cell to cell by sheets Location: Attached to bones intercalated discs Location: Walls of hollow Function: Movement of body in Location: Wall of heart organs and tubes, e.g. stomach relation to external environment Function: Pumping of blood and blood vessels out of heart Function: Movement of contents within hollow organs Sherwood, Figure 8-1 Lecture 32- 4 From Spinal Cord (CNS) to Muscle … Motor neurons and the neuromuscular junction Muscle fibers innervated by red motor neuron Axons of 2 Muscle fibers innervated Muscle d Sp in a l c o r efferent motor Axon by blue motor neuron fiber neurons terminals Neuro- muscular junction Muscle Terminal buttons Neuromuscular Muscle junction fibers Terminal button Axon terminal © Cengage Learning; photo: Ed Reschke/Photolibrary/Getty Images Sherwood, Figure 7-4 Lecture 32- 5 Neuromuscular Junction: main points The junction between the lower motor neuron & muscle fibers. Motor Unit Neurotransmitter = Acetylcholine (Ach) Acetylcholinesterase Formation of the endplate potential - Always excitatory (compare to a synapse in the brain) Initiation of an action potential Relationship to sarcolemma / Transverse (T) tubules Lecture 32- 6  Events at the neuromuscular junction Axon terminal of Action potential propagation motor neuron in motor neuron Myelin sheath 1 Terminal button Voltage-gated Voltage-gated Vesicle of Ca2+ channel Na+ channel Action potential ACh Plasma membrane of Ca2+ propagation muscle fiber in muscle fiber 8 Na+ 2 8 6 7 6 Na 7 3 3 + Acetylcholinesterase 4 4 55 K 9 9 Acetylcholine-gated Na+ receptor-channel (nonspecific cation) Motor end plate Contractile elements within muscle fiber Sherwood Fig 7-5 Lecture 32- 7 Full figure for Muscle Tendon Organization of skeletal muscle your reference, Sherwood 8-2. Muscle fiber (a single Muscle fiber Dark A band muscle cell) Light I band Great summary figure! Myofibril Connective tissue (a) Relationship of a whole muscle and a muscle fiber (b) Relationship of a muscle fiber and a Cross Thin Thick myofibril bridge filament filament M line Z line A band I band Portion of myofibril H zone Thick Thin filament filament Sarcomere A band I band (c) Cytoskeletal M line Cross bridges H zone Z line components of a myofibril Myosin head Z line Titin Thin filament M line Thick filament Z line Myosin tail Thick filament Actin Troponin Tropomyosin Thin filament (d) Protein components of (e) The highly elastic protein titin thick and thin filaments Lecture 32- 8 Organization of skeletal muscle Tendon Muscle Muscle fiber Dark A Light I Muscle fiber band band Myofibril Connective tissue (a) Relationship of a whole (b) Relationship muscle and a muscle fiber of a muscle fiber and a myofibril Relationship of the whole muscle to a muscle fiber then to a myofibril. Striated muscle: A bands & I bands Sherwood 8-2a,b Lecture 32- 9  Muscle fiber A band I band Muscle Muscle fiber Myofibril Connective tissue (b) Relationship of a muscle (a) Relationship of a whole muscle and a muscle fiber fiber and a myofibril Cross bridge Thin filament M line Z line A band I band Thick filament Portion of myofibril H zone Thick Thin filament filament A band I band Sarcomere (c) Cytoskeletal components of a myofibril M line Cross bridges H zone Z line Sherwood 8-2a-c Lecture 32-10 Muscle anatomy: the sarcomere Z line Z line Sarcomere Striated appearance due to different bands: I bands A bands H zone M line H zone A band I band M line Sarcomere: basic functional unit of muscle fiber (from Z line to Z line) Sherwood 8-3 © Cengage Learning; photo: Don W. Fawcett/Science Source Lecture 32-11 Muscle functional anatomy: Thick filament (Myosin) Myosin heads: (a) Myosin molecule: 1. Binds to active sites on Actin-binding site Myosin ATPase site the actin molecules to Hinges form cross-bridges. Heads 2. Hinge region can bend Tail and straighten during contraction. 100 nm 3. Are ATPase enzymes: activity that breaks down adenosine (b) Thick filament: Cross bridges triphosphate (ATP), releasing energy. Part of Myosin molecules the energy is used to bend the hinge region of the myosin molecule during contraction. Lecture 32-12 Muscle functional anatomy: Actin molecules Actin helix Thin Filaments (Actin) (a) Relaxed Binding site for Troponin Troponin attachment with Tropomyosin Actin myosin cross bridge Tropomyosin Myosin cross-bridge Actin-binding site(a) Relaxed: No cross-bridge binding binding sites Myosin cross bridge because cross-bridge binding site on actin is physically covered by troponin–tropomyosin complex. (b) Excited (b) Excited: Muscle fiber is excited = Ca2+ release. Released Ca2+ binds with troponin, pulling troponin–tropomyosin complex aside to expose cross-bridge binding site. Cross-bridge binding occurs. Lecture 32-13 Look at organization of thick vs thin filaments M line Z line A band I band Portion of myofibril H zone Thick Thin filament filament A band I band Sarcomere (c) Cytoskeletal M line Cross bridges H zone Z line components of a myofibril Myosin head Z line Titin Thin filament M line Thick filament Z line Myosin tail Thick filament Actin Troponin Tropomyosin Thin filament (d) Protein components of thick and thin filaments (e) The highly elastic protein titin Sherwood 8-2 Lecture 32- 14  Skeletal Muscle Contraction Contraction = cycles of cross-bridge binding and bending pull thin filaments inward ØSliding filament mechanism Contraction is accomplished by thin filaments from the opposite sides of each sarcomere sliding closer together between the thick filaments ØPower stroke Stroking motion pulls the thin filament toward the center of the sarcomere Lecture 32- 15 Muscle contraction: sarcomere shortening Sliding filament mechanism Sarcomere Z line H zone I band A band Z line Relaxed A band H zone I band same shorter shorter width Contracted Thick filament Thin filament Sarcomere shorter Sherwood Fig 8-7 Lecture 32-16  Actin molecules in thin myofilament Cross-bridge activity 1 Binding: Myosin cross bridge Myosin cross bridge binds to actin molecule. Z line 2 Power stroke: Cross bridge bends, pulling thin myofilament inward. 3 Detachment: Cross bridge detaches at end of power stroke and returns to original conformation. 4 Binding: Cross bridge binds to more distal actin molecule; cycle repeats. (a) Single cross-bridge cycle Sherwood Fig 8-8 Lecture 32-17 Cross bridge activity (b) All cross-bridge stroking directed toward center of thick filament (c) Simultaneous pulling inward of all 6 thin filaments surrounding a thick filament Thin myofilament Thick myofilament Sherwood Fig 8-8b,c Lecture 32- 18 Where does the Ca2+ come from? Surface membrane of muscle fiber Sarcolemma Myofibrils Segments of sarcoplasmic reticulum Lateral Transverse (T) sacs tubule I band A band I band Sherwood Fig 8-9 Lecture 32-19 Excitation-Contraction Coupling 1. AP at NMJ causes release 1 An action potential arriving at a terminal button of the neuromuscular junction 2 The action potential moves across the surface membrane and into the muscle fiber’s of ACh, triggers AP in Acetylcholine stimulates release of acetylcholine, which diffuses across the cleft and triggers an action potential in the muscle fiber. interior through the T tubules. An action potential in the T tubule triggers release of Ca2+ the sarcoplasmic reticulum into the cytosol. from muscle fiber Terminal button Plasma membrane of muscle cell 2. AP moves across the T tubule Lateral sac of sarcoplasmic surface membrane into the reticulum interior through T tubules. APs in the T tubules trigger Acetylcholine-gated Neuromuscular Motor end Ca2+ release of Ca2+ from the receptor-channel junction plate pump for cations sarcoplasmic reticulum. 8 When action potentials Ca 2+ Ca 2+ Ca2+ -release channel stop, Ca2+ is taken up by the 3. Ca2+ binds to troponin on sarcoplasmic reticulum. With no Ca2+ on troponin, tropomyosin moves back to Tropomyosin Ca 2+ Ca 2+ Troponin thin filaments. its original position, blocking myosin cross-bridge binding Thin filament Myosin sites on actin. Contraction Actin molecule stops and the thin filaments cross bridge 4. Tropomyosin shifts, reveals passively slide back to their original relaxed positions. Thick filament myosin cross bridge sites 3 Ca2+ binds to troponin on 5. Myosin cross bridges attach thin filaments. Myosin cross-bridge binding site 6. Power stroke (ATP used) Actin-binding site 7. Cross bridge detaches Cycle repeats 7 After the power stroke, the cross bridge detaches from actin. If Ca2+ is still 4 Ca2+ binding to 8. When APs stop, Ca2+ taken present, the cycle returns to step 5. troponin causes tropo- myosin to change shape, physically moving it away back up by sarcoplasmic from its blocking position; this uncovers the binding sites on actin for the reticulum. Contraction myosin cross bridges. stops Thin filaments passively reset 6 The binding triggers the cross bridge to bend, pulling the thin filament over the thick filament toward the center of the sarcomere. This power 5 Myosin cross bridges attach to stroke is powered by energy provided by ATP. actin at the exposed binding sites. Sherwood Fig 8-11 Lecture 32- 20  Calcium Is the Link Between Excitation and Contraction Spread of action potential down transverse tubules Calcium release from sarcoplasmic reticulum ATP-powered cross-bridge cycling Rigor mortis and relaxation Contractile activity far outlasts the electrical activity that initiated it Lecture 32- 21 Cross bridge cycle 1 Energized: ATP split by myosin ATPase; ADP and Pi remain attached to myosin; Note ATP necessary! energy stored in cross bridge ADP...or... No Ca2+ ADP y y (that is, energy “cocks” cross erg erg En En bridge). 2b Resting: No excitation; no Ca2+ released; actin and myosin prevented from binding; no cross-bridge cycle; muscle fiber remains at rest. present (excitation) 4a Detachment: Linkage between actin and myosin broken as fresh Cross- ADP y erg molecule of ATP binds to myosin bridge En cross bridge; cross bridge assumes cycle original conformation; ATP 2a Binding: Ca2+ released on hydrolyzed (cycle starts again at excitation; removes inhibitory step 1). Influence from actin, enabling it to bind with cross bridge. ADP Fresh ATP available Energy 3 Bending: Power stroke of...or... cross bridge triggered on contact between myosin and actin; Pi released during and ADP No ATP (after death) released after power stroke. 4b Rigor complex: If no fresh ATP available (after death), actin and myosin remain bound in rigor complex. Sherwood, Fig 8-12 Lecture 32- 22 Just FYI if you need it – Metabolic pathways producing ATP used during muscle contraction/relaxation 3. Metabolic pathways that supply ATP: 3a. Transfer of a high- energy phosphate from creatine phosphate to ADP 3b. Oxidative phosphorylation (O2 present) fueled by glucose derived from muscle glycogen stores or by glucose and fatty acids delivered by the blood 3c. Glycolysis (O2 absent). Pyruvate converted to lactate Sherwood, Fig 8-21 Lecture 32-23 Lecture 32- 24 Skeletal Muscle Pathophysiology & Movement Disorders Adobe Stock October 22, 2024 Instructional materials ©Kim Nixon, Ph.D., 2022 Lectures 33-34 1  Objectives-Skeletal Muscle Pathophysiology & Movement Disorders 1. Pathophys. For each disorder differentiate based on: Definition and basic epidemiology Key symptoms Essential pathophysiology – what is the basic mech of pathology? Any issues/points pertinent to pharmacy 2. Additional points for Parkinson’s Disease: apply knowledge of dopamine systems to understand the strengths and weaknesses of the DA theory of Parkinson’s Disease. indirect vs direct paths in the basal ganglia Differentiate the mechanism of action of the primary treatment approaches by drug classes. (DA replacement therapy, DA agonists, Muscarinic antagonists) Appreciate why Dopamine is a delicate balance in CNS function. 3. For ALS, Muscular Dystrophy and Huntington’s disease – only need to know definition and be able to differentiate from other muscle/movement disorders. Resources: Sherwood Chapter 7 (NMJ), 8; Pathophys Text or PDFs on canvas Lectures 33-34 2 Muscle & Movement Disorders Idiopathic vs. iatrogenic Muscle disorders Movement disorders Rhabdomyolysis Peripheral neuropathy Muscular Dystrophy Parkinson’s disease (definition only) Tardive dyskinesia ALS (definition only) Huntington’s disease (definition only) Both? Myasthenia gravis Neither (Neurological / neuroimmune disorder) Multiple Sclerosis Lectures 33-34 3 Rhabdomyolysis Rare (26K/yr) life-threatening muscle degeneration. Damage from overexertion, trauma, toxins, dehydration, medications / drug interactions, prolonged bed rest Risk factors: endurance athletes, firefighters, construction workers, military, age (elderly) Muscle cell disintegration à myoglobin release. High [Myoglobin] à kidney failure and death. Symptoms - Muscle soreness “myalgia” - Muscle weakness All 3 - Dark urine (“tea colored” brown to red w/o hematuria) 11x creatine kinase in blood Treatments: IV fluids, dialysis (if severe), eliminate cause Lectures 33-34 4 Rhabdo in the news… Incident Year 12 Tufts Lacrosse Players 2024 1 Bucknell University Football Player 2024 Died! 3 University of Oregon Football Players 2016 8 Texas Women's University Volleyball Players 2016 13 University of Iowa Football Players 2011 24 McMinnville High School (Ore) Football Players 2010 Lectures 33-34 5 Medications with rhabdomyolysis as an ADR: Statin-induced rhabdomyolysis: Risk factors: high dose, age, female, renal or hepatic insufficiency, diabetes mellitus, taking with other cytochrome p450 (3A4) inhibitors Lectures 33-34 6  Pathophys of Rhabdomyolysis Muscle cell disintegration à myoglobin release High [myglobin] leads to kidney failure and death. Damage Physiological Death processes: mechanisms: effect: Parekh et al., 2012 Emerg Med Pract Lectures 33-34 7 Myasthenia Gravis (MG) Autoimmune disorder of neuromuscular transmission, that results in skeletal muscle weakness Relatively rare: 31K-67K U.S. (150-205/1mil worldwide) Risk factors: Family history of autoimmune disease. Men >60; women F) Genetic: 100s of genes, ~30% causal Environment: vitamin D deficiency, particular viral infections (EBV esp), smoking, high dietary sodium, circadian disruption Does not diminish life expectancy; 2ndary complications can Diagnosis: Diagnosis of exclusion. No single test. “2 episodes of neurologic disturbance reflecting distinct sites of CNS damage that cannot be explained by another mechanism1” Types: Relapse Remitting (RRMS) Both Primary Progressive (PPMS ~15%) Lectures 33-34 12 MS: Symptoms Primary symptoms – direct consequence of conduction disturbance. Reflect what axons are damaged - Paresthesias - Vision problems/optic neuritis* - Weakness - Psychological changes - Spasticity - Cognitive changes - Ataxia - Fatigue - Gait problems and falls - Dizziness, vertigo “light headed” - Pain - Bowel/bladder dysfunction - Speech difficulty - Sexual dysfunction Secondary symptoms – complications from primary -UTIs, respiratory infections, poor nutrition, depression Tertiary symptoms – impact of the disease on life -e.g. depression; inability to work; social withdrawal Lectures 33-34 13 MS: Pathophysiology Inflammatory demyelinating disease of CNS white matter Demyelination Oligodendrocyte loss White matter plaques with reactive gliosis Mononuclear cell infiltration Axonal loss Healthy neuron MS neuron Lectures 33-34 14 Peripheral Neuropathy Umbrella term for >100 conditions that involve damage to the nerves of the PNS. Symptomatic or idiopathic Many causes: - Diabetic – most common cause - Injury - Inflammatory - Toxins (e.g. excess alcohol use) - ADR to some chemotherapies - Infections (e.g. varicella-zoster, West Nile, HSV, Lyme disease, HIV) Host of pharmacological approaches Lectures 33-34 15 Peripheral Neuropathy: Symptoms Symptom severity progression and prognosis depend on the cause and type of nerve damaged. Ranges: mild to disabling Loss of reflexes, numbness, tingling, pain or problems with sensation, e.g. feeling changes in temperature or touch. Classifications: - Predominantly motor (muscle weakness or atrophy, cramps, twitching) - Sensory (loss of somatosensation, typically hands/feet - Sensory-motor - Autonomic (excess sweating, heat intolerance, GI symptoms, BP) Lectures 33-34 16 Parkinson’s Disease Slow progressive degeneration of the nigrostriatal dopamine pathway. Parkinsonian versus Parkinson’s Disease (iatrogenic) (idiopathic) 500,000+ affected Sporadic vs Early Onset (familial? 5-10%) risk factors: age (onset ~60), Male>Female. Not fatal per se, but complications are Lectures 33-34 17 Parkinson’s Disease Falls become likely! Motor Signs = TRAP 1. Tremor 2. Rigidity 3. Akinesia (bradykinesia) 4. Posture Reflex 5. Festinating gait 6. Hypophonia 7. Dysarthria 8. Dysphagia 9. Hypomimia ”mask” Lectures 33-34 18 ANATOMY OF PD Slow progressive degeneration of the nigrostriatal dopamine pathway. The basal ganglia are the brain regions that modulate voluntary movement initiation. Caudate nucleus striatum Putamen Globus pallidus Substantia nigra Subthalamic nucleus In PD the balance between excitation and inhibition in the basal ganglia is lost. Lectures 33-34 19 Parkinson's Disease - Pathophysiology Premotor phase Symptomatic PD Clinically defined PD does not occur until about 70-80% of of nigral DA levels are lost Lectures 33-3420 PD Pathology: Direct vs. indirect pathway D1 D2 é movement Glutamate GABA Dopamine D1 D2 D1 D2 ê movement Take home message: Direct pathway: enables movement Indirect pathway: inhibits movement Outcome: low dopamine impairs movement Lectures 33-34 21  Pharmacological Strategies in PD ↑Dopaminergic neurotransmission - DA replacement therapy (L-Dopa) - Direct acting DA D2 receptor agonists - Reduce the rate of DA catabolism Other systems - Anti-cholinergics (M1 antagonists) - Amantadine (MOA?, Symmetrel®) Note: non pharmacological approaches too – PT and speech therapy Lectures 33-34 22  DA neurotrans… 1. Dopamine replacement therapy (L-Dopa) 2. DA receptor agonists 3. Reduce DA catabolism MAO inhibitors COMT inhibitors Lectures 33-34 23 Tardive Dyskinesia Involuntary, repetitive excessive movements Iatrogenic! Prolonged Dopamine receptor antagonism - traditional antipsychotics - some anticholinergics and SSRIs Slowly reversible alteration in DA receptor function Delicate balance - need to treat psych condition but not produce T.D. New therapeutics! VMAT-2 inhibitors. Lectures 33-34 24 Lectures 33-34 25 Schematic wiring of the Basal Ganglia Note: Indirect (D2) v direct (D1) path Normal BG activity: 1. Vol Movement executed by Primary Motor Ctx 2. Nigrostriatal tract 3. BG input to ctx is via thalamus 1. 2. 3. Key: reduced activity less active increased activity less inhibitory signaling onto the Gpi/SNpr RELEASES IT FROM INHIBITION Lectures 33-34 26 Muscular Dystrophy Heterogenous group of hereditary, progressive muscle degeneration disorders Progressive weakness and atrophy of skeletal muscles (red = degeneration): 5-6/100K individuals (DMD: 1/5000 male births) Childhood onset (@ 3-5y), mostly boys; some rare adult onset Duchenne’s MD (DMD): due to Mutation in dystrophin Life expectancy reduced (~ 20s-30s) a structural muscle protein. Genetic: e.g. X-linked recessive mutation in - Connects the sarcolemma dystrophin gene (DMD); 25% sporadic with the sarcomere. Diagnosis: Muscle biopsy, lack of dystrophin - “shock absorber” from the protein. mechanical stress of muscle contraction. No cure Muscle fibers show increased - treatments primarily PT, OT. “tearing” - Symptom management. Corticosteroids. Progressive necrosis of muscle Types: Duchenne’s (DMD; largest group), fibers outpaces repair Becker (BMD – later onset, milder?) Chemello et al., 2020; J Clinical Investigation Lectures 33-34 27 Amyotrophic Lateral Sclerosis “Lou Gherig’s Disease” Rapidly progressing and fatal Motor Neuron Disease Death w/in 5 years; respiratory muscle failure Genetic? Only 5-10% hereditary (mutation in SOD1) Risk factors: toxin exposure ± strenuous activity? Athletes? Veterans? Smoking? No known cause, treatment or cure Motor Symptoms: Muscle weakness, spasticity, dysphagia, dysarthria Non-motor Symptoms: Cognitive impairments (~50%) Pathophys = Degeneration of upper & lower motor neurons - ~50% of spinal motor neurons lost - Microgliosis and astrogliosis (glial reactions) - Subsequent degeneration of motor cortex and ventral roots of spinal cord New research on causes? Protein inclusions “TDP43 proteinopathy,” RNA processing or metabolism disorder, or loss of astrocytic glutamate transporters? Lectures 33-34 28 Huntington’s Disease Hereditary neurodegenerative disease that causes severe chorea and progressive dementia - autosomal dominant gene mutation on chromosome 4 - A trinucleotide repeat disorder results in Huntingtin (HTT) gene Causes degeneration of interneurons in striatum - impaired clearance of protein aggregates → excitotoxicity → mitochondrial dysfunction = too much dopamine. Age of onset: middle age No treatment or cure. Ease symptoms: - DA Antagonists (antipsychotics) – motor dysfunction - Antidepressants – mood disorders - ????? – cognitive impairments Lectures 33-34  Psychosis (Schizophrenia) October 24, 2024 © instructional content, Kimberly Nixon, Ph.D. 2022 35 - Psychosis 1  Objectives: Schizophrenia 1. Apply knowledge of neurotransmission: Glutamate, DA, 5HT 2. Understand the pathophysiology of Schizophrenia: – Basic epidemiology/stats – Symptoms (positive vs negative vs cognitive) – Neuropathologies – Dopamine vs Glutamate vs Serotonin Hypotheses 3. Differentiate the mechanism of action of the primary treatment approaches or drug discovery approaches by drug classes. DA antagonists vs potential Glutamatergic approaches. 4. Appreciate why Dopamine is a delicate balance in CNS function. Resources: NIMH Schizophrenia page: https://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml Nature Reviews Disease Primers: Schizophrenia (2015). PDF posted in Canvas. – much more detail than needed, but includes therapeutics. 35 - Psychosis 2 Schizophrenia – Definitions/Epidemiology Likely a heterogeneous collection of several poorly defined/understood diseases Disorder of thought, NOT “split personality.” Affects ~1% of the population (≈M/F) Neurodevelopmental? – Children who later develop schizophrenia have abnormal emotional reactions very early (less positive and more negative affect) – Onset in early adulthood (16-25) Debilitating and life-long disabling. Complete recovery from schizophrenia is rare. 35 - Psychosis 3  Clinical Features / Symptoms Positive symptoms Positive symptoms Negative symptoms Delusions (often paranoid) Cognitive impairments Hallucinations (auditory common) Thought disorder - delusions of grandeur - wild trains of thought - irrational conclusions - rambling speech Abnormal, disorganized behavior and/or speech Catatonia The diagnosis of schizophrenia is one of exclusion 35 - Psychosis 4  Clinical Features / Symptoms Positive symptoms Negative symptoms Negative symptoms Cognitive impairments Socially withdrawn Flattened affect Anhedonia Avolition Cognitive impairments Attention Memory Comprehension/understanding 35 - Psychosis 5  DSM-5-TR diagnostic criteria 2+ core symptoms for >1 month Positive *must include 1 of these Delusions Impaired function in work, interpersonal Hallucinations relationships or self-care Thought disorder: -Disorganized Speech -Disorganized behavior Catatonic behavior Hallucinations Disorganized or catatonic Negative *Delusions Flat affect Core behavior Social withdrawal Symptoms Avolition *Disorganized Negative Anhedonia Speech Symptoms Cognitive Memory impairment Learning impairment Attention problems Lack of understanding 35 - Psychosis 6  Devt time course of pathology diagnosis adolescence Emerging adult Correll & Scholler, 2020; Neuropsychiatric Disease & Treatment 35 - Psychosis 7  Causes? Risk Factors ~50-80% Familial Heritable? – 20 - 150 possible genes ~20-50% Neuregulin (glutamatergic signaling) Idiopathic dysbindin (tethering of NMDAR) DISC-1 “disrupted in schizophrenia 1” (cell migration, neurite outgrowth & receptor trafficking) – Co-inheritance ~50% for MZ twins; 10% for DZ twins Environmental risk factors: – Prenatal viral infection (e.g. 2nd trimester flu) – Poor maternal and perinatal nutrition – Perinatal hypoxia or other birth trauma – Illicit drug use (esp early use of cannabis) – Psychological stress – Advanced paternal age, birth order/winter birth 35 - Psychosis 8 Neuropathology Frontal Lobe Neurodegeneration? - Enlarged lateral ventricles - Slight reduction in thickness of cortical gray matter - Hypofrontality Loss of grey matter elsewhere: MRI scans of 28yo male identical twins insular cortex, thalamus, striatum showing the enlarged brain ventricles in the twin with schizophrenia (R) compared to his well brother (L). (Torrey & Weinberger) Hyperactive DA system? Serotonergic Dysfunction? pharmacotherapies Glutamate Hypofunction? Fig: edited from Rebecca Clements, Harvard U. 35 - Psychosis 9 Dopamine Theory of Schizophrenia Carlsson – indirect evidence of overactive DA system. (2000 Nobel) Success of 1st gen. antipsychotics – D2 receptor antagonists – on positive symptoms Stimulants (e.g. amphetamines. causes excess DA release) produce a behaviors similar to a schizophrenic episode in humans. Side effects of L-Dopa include hallucinations Inferring something about disease pathogenesis from the actions of a drug that reduces symptoms is not scientifically sound Mesocortical Mesolimbic Nigrostriatal 35 - Psychosis 10  Dopamine Receptors D1 receptor family D2 receptor family D1 & D5 receptors: Gs D2, D3 & D4 receptors: Gi - increase cAMP - decrease cAMP - typically postsynaptic - presynaptic & postsynaptic - Located in the Substantia - Located in the Substantia Nigra, Striatum, Frontal Nigra, Striatum, Prefrontal Cortex, Hypothalamus Cortex, Limbic System, VTA, Pituitary G&G Fig 13-8 35 - Psychosis 11 1st generation anti-psychotics = D2 antagonists 35 - Psychosis 12  Limitations of the Dopamine Hypotheses Hallucinogens (LSD, psilocybin) and dissociative anesthetics (PCP, ketamine), also cause psychotic symptoms. PCP (NMDAR antag) produces a psychotic syndrome that models schizophrenic psychosis more accurately than amphetamine D2-receptor blockade occurs rapidly after antipsychotic 🤷 dosing, but clinical response typically requires several weeks Postmortem studies of patients with schizophrenia have not found consistent abnormalities in the density of any of DA receptor subtype Positron emission tomography (PET) imaging, has not shown any increase in the density of D2 receptors in schizophrenia. Limitation of D2 antagonism, ADRs: EP movement disorder, tardive dyskinesia Balance of DA! 35 - Psychosis 13  Glutamate Hypofunction Theory of Schizophrenia Postmortem changes observed include: – Decreased glutamate in CSF – Decreased NMDA receptors NMDAR hypofunction thought to reduce activity of mesocortical DA neurons but DA Systems Mesocortical increase activity of mesolimbic DA neurons. Mesolimbic Nigrostriatal NMDA-Receptor antagonists (PCP, ketamine, dizocilpine) produce both positive and negative symptoms. Rodent models of reduced/antagonized NMDAR = stereotypy, ⇓ social interaction. Antipsychotics reverse this. LIMITATION: drug discovery tricky. Excess glutamate is toxic! 35 - Psychosis 14  Ionotropic Glutamate Receptors AMPA Kainate NMDA Ion channel Na+ Na+ Ca2+ Endogenous Glutamate Co Glutamate Glutamate Glycine -a Agonist Aspartate g on ist Other AMPA Kainate NMDA Agonists Presynaptic Few presynaptic Location* Postsynaptic Postsynaptic Postsynaptic Glia Glia Fast EPSP Slow EPSP Function Fast EPSP Presynaptic Inhibition Synaptic Plasticity (LTP) 35 - Psychosis 15 Metabotropic glutamate receptors (mGluRs) GPCRs! Gq Gi Gi Intense area of drug development Adapted from Muguruza et al., 2016; Frontiers in Pharmacology 35 - Psychosis 16 The Serotonin Hypothesis of Schizophrenia - Lysergic acid diethyl amide (LSD), psilocybin, and mescaline are agonists at 5-HT2A receptors, and cause sensory disruptions that lead to hallucinations (though mostly visual). - Success of the 5HT2A Serotonin antagonists. Atypical Antipsychotics: (high 5HT2A antags) Antipsychotic effects with no extrapyramidal adverse responses, and very low chance of developing tardive dyskinesia - Clozapine (Clozaril®) Weak D2 antagonist, high affinity 5-HT2A antagonist (atypical anti-psychotic) 35 - Psychosis 17 E,F A,B Gi Gq Gs 35 - Psychosis 18  Addiction Kimberly Nixon, Ph.D. 10-24-24 Amended! © Kimberly Nixon 10-24-24Addiction 36-1  Objectives - Addiction 1. Understand what addiction is and general related terms. 2. Know the common misused substances and alcohol and their primary mechanism of action (see notes of slide #13 for exactly what you need to know) 3. Appreciate which of the agents discussed today is our biggest problem – greatest harm, most overdoses, greatest use disorder. 4. What is the mesolimbic dopamine system and differentiate it from the other dopamine systems. 5. Appreciate that all “addictive” drugs increase dopamine but they each do it uniquely in the mesolimbic reward system. More info at https://www.niaaa.nih.gov/ and https://nida.nih.gov/ Addiction 36- 2  What is addiction? Substance misuse? Drug addiction is a chronic, relapsing disorder characterized by compulsive drug use, despite harmful or negative consequences. While the initial decision to take drugs is voluntary, repeated drug use changes the brain in such a way to impair behavioral control processes and interfere with one’s ability to resist intense urges (craving) to take drugs. Addiction doesn’t discriminate though some populations are at greater risks than others. Risk factors: - age (starting use in adolescence) - genes (especially for alcohol in males) - environment (stress, adversity) https://www.drugabuse.gov/publications/drugfacts/understanding-drug-use-addiction Addiction 36- 3  Addiction: Terms & Definitions Addiction (AUD; SUD = person first terminology) Tolerance Relative Effect Dependence - Psychological Tolerance - Physical - Withdrawal Relapse Dose Addiction 36- 4  Common Misused Substances Hallucinogens (Ketamine, LSD, PCP, MDMA “Ecstasy”) Marijuan