Psych Electrophysiology 2020 final

1. MD Psych - Neurophysiology 1. Electrophysiology 2. Synapse & NMJ 3. Neurotransmitters 4. Sensory functions 5. Physiology of Pain 6. Main Motor system 7. Basal Ganglia 8. Cerebellum 9. Posture 10.Higher functions 11.Sleep, arousal 12.Memory and emotions 13.Evoked potentials Prof. Vajira Weerasinghe Senior Professor of Physiology Faculty of Medicine, University of Peradeniya & Consultant Neurophysiologist, Teaching Hospital, Peradeniya www.slideshare.net/vajira54 vajira54@gmail.com

2. • www.slideshare.net/vajira54 • vajira54@gmail.com • .edu • …..ac.uk

3. Membrane potential • Excitable tissues have more negative RMP ( - 70 to - 90 mV) Non-excitable Red cell GIT excitable neuron muscle • Non-excitable tissues have less negative RMP ( - 5 to -10 mV) All biological membranes have a resting membrane potential across the membrane with the inside being more negative than the outside

4. Factors contributing to RMP • One of the main factors is K+ efflux which causes negativity inside the membrane (Nernst Potential: -94mV) through leak channels (there are more K+ leak channels than Na+ leak channels) • Na+/K+ pump causes more negativity inside the membrane (3 Na+ removed with 2 K+ replaced, excess negativity inside) • Negatively charged protein remaining inside due to impermeability contributes to the negativity inside the membrane • Contribution of Na+ influx is little (Nernst Potential: +61mV) and causes less negativity inside the membrane • Net result: -70 mV inside

5. Na/K pump • Active transport system for Na+/K+ exchange using energy • It is an electrogenic pump since 3 Na+ influx coupled with 2 K+ efflux • Net effect of causing negative charge inside the membrane 3 Na+ 2 K+ ATP ADP What is the action of Na+/K+ pump blockers? QUIZ

6. -70 +35 RMP Hyperpolarisation Slow depolarisation Threshold -55 Action potential Time (ms) (mV) Opening of Voltage gated Na+ channel Closure of Voltage gated Na+ channel & opening of voltage gated K+ channel Closure of voltage gated K+ channel Compare nerve AP with AP of SA node and cardiac muscle QUIZ 6

7. • At rest: the activation gate is closed • At threshold level: activation gate opens – Na+ influx will occur – Na+ permeability increases to 500 fold • when reaching +35, inactivation gate closes – Na+ influx stops • Inactivation gate will not reopen until resting membrane potential is reached outside inside outside inside -70 Threshold level +35 Na+ Na+ outside inside Na+m gate h gate What is the action of voltage gated Na+ channel blockers? QUIZ

8. • At rest: K+ channel is closed • At +35 – K+ channel open up slowly – This slow activation causes K+ efflux • After reaching the resting phase, still some K+ channels may remain open: causing further hyperpolarisation outside inside outside inside -70 At +35 K+ K+ n gate During repolarisation phase, at -55 mV Na+ channels do not open again. What is the reason? QUIZ -70 +35

9. Propagation of AP • When one area is depolarised • A potential difference exists between that site and the adjacent membrane • A local current flow is initiated • Local circuit is completed by extra cellular fluid

10. AP propagation along myelinated nerves • Local current will flow one node to another • Thus propagation of A.P. is faster. Conduction through myelinated fibres also faster. • Known as Saltatory Conduction

11. 11

12. 13

13. Demyelinating disorders • Peripheral demyelination – Guillain Barre Syndrome (GBS) or Acute Inflammatory Demyelinating Polyneuropathy (AIDP) – Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) – Multifocal Motor Neuropathy (MMN) – Multifocal Acquired Demyelinating Sensorimotor Neuropathy (MADSAM) – Distal Acquired Demyelinating Symmetric Neuropathy (DADS) – POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) • Central demyelination – Multiple Sclerosis (MS) – Optic neuritis – Acute disseminated encephalomyelitis (ADEM) – Adrenoleukodystrophy

14. Applied physiology • Decreasing the external Na+ concentration reduces the size of the action potential but has little effect on the resting membrane potential • If the extracellular level of K+ is increased (hyperkalemia),the resting potential moves closer to the threshold for eliciting an action potential, thus the neuron becomes more excitable • If the extracellular level of K+ is decreased (hypokalemia),the membrane potential is reduced and the neuron is hyperpolarized

15. Nerve fibre types 16

22. Membrane stabilisers • Membrane stabilisers (these decrease excitability) • Increased serum Ca++ – Hypocalcaemia causes membrane instability and spontaneous activation of nerve membrane – Reduced Ca level facilitates Na entry – Spontaneous activation • Decreased serum K+ • Local anaesthetics • Acidosis • Hypoxia • Membrane destabilisers (these increase excitability) • Decreased serum Ca++ • Increased serum K+ • Alkalosis • Caffeine • strychnine

23. Synapse • Synapse is a gap between two neurons • More commonly chemical • Rarely they could be electrical (with gap junctions) – which are pores (as shown in the electron micrograph) constructed of connexin proteins

24. Different types of synapses 25

25. Types of synapses • Axo-dendritic synapse • Most common • Axon terminal branch (presynaptic element) synapses on a dendrite • Axo-somatic synapse • Axon terminal branch synapses on a soma (cell body) • Axo-axonic synapse • Axon terminal branch synapses on another axon terminal branch (for presynaptic inhibition) • Dendro-dendritic synapse • Dendrite synapsing on another dendrite (localised effect) 26

26. Details of presynaptic events • in the resting state, the presynaptic membrane has resting membrane potential • when an action potential arrives at the end of the axon • the adjacent presynaptic membrane is depolarised • voltage-gated Ca2+ channels open and allow Ca2+ influx (driven by [Ca2+] gradient) • elevated [Ca2+] activates synaptic proteins (SNARE proteins: Synaptobrevin, Syntaxin, SNAP 25) and triggers vesicle mobilization and docking with the plasma membrane • vesicles fuse with presynaptic plasma membrane and release neurotransmitter molecules (about 5,000 per vesicle) by exocytosis • neurotransmitter molecules diffuse across the cleft & bind with postsynaptic receptor proteins • neurotransmitter molecules are eliminated from synaptic clefts via pinocytotic uptake by presynaptic or glial processes and/or via enzymatic degradation at the postsynaptic membrane • molecules are recycled • subsequently, presynaptic plasma membrane repolarises

27. Ca2+ Ca2+ SNARE proteins 28

28. IONOTROPIC RECEPTORS • Neurotransmitter molecule binds to the receptor • Cause a ligand-gated ion channel to open • Become permeable to either sodium, potassium or chloride • Accordingly depolarisation (excitation) or hyperpolarisation (inhibition) • Quick action, short lasting

29. • Neurotransmitter attaches to G-protein-coupled receptors (GPCR) which has slower, longer- lasting and diverse postsynaptic effects • They can have effects that change an entire cell’s metabolism • Activates enzymes that trigger internal metabolic change inside the cell • Activate cAMP • Activate cellular genes: forms more receptor proteins • Activate protein kinase: decrease the number of proteins • Sometimes open up ion channels also Metabotropic Receptors

30. Postsynaptic activity • Synaptic integration – On average, each neuron in the brain receives about 10,000 synaptic connections from other neurons – Many (but probably not all) of these connections may be active at any given time – Each neuron produces only one output – One single input is usually not sufficient to trigger this output – The neuron must integrate a large number of synaptic inputs and “decide” whether to produce an output or not – Constant interplay of excitatory and inhibitory activity on the postsynaptic neuron produces a fluctuating membrane potential that is the algebraic sum of the hyperpolarizing and depolarizing activities – Soma of the neuron thus acts as an integrator

31. 32

32. Other synaptic activities • Postsynaptic inhibition – eg. GABA activates GABA A receptors on the postsynaptic membrane and opens up Cl- channels and causes hyperpolarisation and inhibition • Presynaptic inhibition – eg. GABA activates GABA B receptors on the presynaptic membrane and through G proten activation opens up K+ channels and causes hyperpolarisation and inhibition • Autoreceptors – eg. Ach released from the presynaptic membrane activates autoreceptors for Ach on the presynaptic membrane and causes feedback inhibition • Renshaw cell inhibition – Spinal motor neuron activates a collalteral neuron which secrete glycine and which inhibit activity of the spinal motor neuron • Retrograde signalling – Neurotransmitter secreted from the postsynaptic membrane act on the receptor on the presynaptic membrane and through G protein activation causes inhibition

33. Dendritic spine • Small button like extensions like “door knobs” found on the dendritic processes that contain post-synaptic densities • Axo-dendritic synapses terminates in these • Dendritic spines are known to change shape, to the extend of appearing and disappearing entirely & is the basis of memory • A mechanism underlying memory loss in Alzheimer's disease involves a loss of dendritic spines in hippocampal pyramidal cells • Ca channels, NMDA receptors are present in these • Long-term potentiation (LTP) at Hebbian synapses in hippocampal region CA1 occurs involving NMDA receptors in these sites

34. Neuromuscular junction

35. NMJ function • Pre-synaptic membrane • Ca2+ channels • SNARE proteins • Acetylcholine release • Postsynaptic membrane • Acetylcholine receptors • Ligand-gated Na+ channels • Synaptic cleft • cholinesterase

36. Ach vesicle docking • With the help of Ca entering the presynaptic terminal • Docking of Ach vesicles occur • Docking: – Vesicles move toward & interact with membrane of presynaptic terminal • There are many proteins necessary for this purpose • These are called SNARE (soluble NSF attachment protein receptor) proteins – Syntaxin, synaptobrevin, SNAP25 • Botulinum toxin cleaves all three SNARE proteins • Tetanus toxin causes cleavage of synaptobrevin • Deficiency of SNARE proteins has been linked with schizophrenia causing altered dopamine or glutamate release • Ii is also linked with psychosis

37. NMJ • Postsynaptic membrane contain nicotinic acetylcholine receptor • This receptor contains several sub units (2 alpha, beta, gamma, delta) • Ach binds to alpha subunit • Na+ channel opens up • Na+ influx occurs • End Plate Potential (EPP) •This is a graded potential •Once this reaches the threshold level •AP is generated at the postsynaptic membrane

38. NMJ blocking • Useful in general anaesthesia to facilitate inserting tubes • Muscle paralysis is useful in performing surgery • Commonly used to paralyze patients requiring intubation whether in an emergency as a life-saving intervention or for a scheduled surgery and procedure • Indications for intubation during an emergency – failure to maintain or protect the airway – failure to adequately ventilate or oxygenate – anticipation of a decline in clinical status

39. Earliest known NMJ blocker - Curare • Curare has long been used in South America as an extremely potent arrow poison • Darts were tipped with curare and then accurately fired through blowguns made of bamboo • Death for birds would take one to two minutes, small mammals up to ten minutes, and large mammals up to 20 minutes • NMJ blocker used in patients is tubocurarine

40. Non-depolarising blocking agents – Competitive – Act by competing with Ach for the Ach receptors – Binds to Ach receptors and blocks – Prevent Ach from attaching to its receptors – No depolarisation – Late onset, prolonged action – Ach can compete & the effect overcomes by an excess Ach – Anticholinesterases can reverse the action – eg. • Curare • Atracurium • Rocuronium • Vencuronium

41. Depolarising blocking agents – non-competitive, chemically act like Ach – Bind to motor end plate and once depolarises – Persistent depolarisation leads to a block • Due to inactivation of Na channels – Phase I block • After a depolarizing agent binds to the motor end plate receptor, the agent remains bound and thus the end plate cannot repolarize • during this depolarizing phase the transient muscle fasciculation occur • Absence of fade to tetanic stimulation – Phase II block • After adequate depolarization has occurred, phase II (desensitizing phase) sets in and the muscles are no longer receptive to acetylcholine released by the motor neurons • It is at this point that the depolarizing agent has fully achieved paralysis • Fade after tetanic stimulation – Ach cannot compete – Quick action start within 30 sec, recover within 3 min and is complete within 12– 15 min – Hydrolysed by plasma cholinesterase (also called pseudocholinesterase) produced in the liver – Prolonged blockade is seen in liver disease or pregnancy – Inhibition of plasma cholinesterase occurs with OP compounds – eg. Succinylcholine – Side effect: hyperkalaemia – Bind to nicotinic and muscarinic Ach, causes bradycardia – Contraindicated in burns

42. Na+ Acetylcholine Depolarization Na+ - - - -+ + + + - - - - + + + + + + + + + + + +- - - - - - - - 43

43. Na+ AcetylcholineTubocurarine Na+ + + + + - - - -- - - - + + + + Competitive neuromuscular blocking drugs 44

44. Na+ Depolarized Na+ PHASE I Membrane depolarizes resulting in an initial discharge which produces transient fasciculations followed by flaccid paralysis - - - - + + + ++ + + + - - - - - - - -+ + + + + + + + - - - -- - - - Depolarizing Neuromuscular blocking drugs

45. Repolarized PHASE II Membrane repolarizes but the receptor is desensitized to effect of acetylcholine + + + +- - - -+ + + +- - - - - - - -+ + + + - - - -+ + + + Depolarizing Neuromuscular blocking drugs

46. Anticholinesterases • AchE inhibitors – Inhibit AchE so that Ach accumulates and causes depolarising block • Reversible – Competitive inhibitors of AChE • eg. physostigmine, neostigmine, edrophonium used to diagnose and treat myasthenia • Irreversible – Binds to AChE irreversibly • eg. Insecticides (organophosphates), nerve gases (sarin)

47. NMJ disorders • Myasthenia gravis (MG) – Antibodies to Ach receptors – Post synaptic disorder • Lambert Eaton myasthenic syndrome (LEMS) – Presynaptic disorder (antibodies against Ca channels) • Neuromyotonia (Isaac’s syndrome) – Down-regulation of K+ channels, hyperexcitability due to prolonged depolarisation • Botulism – Presynaptic disorder – Binds to the presynatic region, cleaves SNARE proteins and prevent release of Ach • Tetanus – Presynaptic disorder – Blockade of neurotransmitter release (GABA & glycine) of spinal inhibitory neurons causes hyper-excitable tetanic muscle contractions

48. Botulinum toxin • Most potent neurotoxin known • Produced by bacterium Clostridium botulinum • Causes severe diarrhoeal disease called botulism • Action: – enters into the presynaptic terminal – cleaves proteins (syntaxin, synaptobrevin, SNAP 25) necessary for Ach vesicle release with Ca2+ • Chemical extract is useful for reducing muscle spasms, muscle spasticity and even removing wrinkles (in cosmetic and plastic surgery)

49. 50

50. Organophosphates • Phosphates used as insecticides • Action – AchE inhibitors – Therefore there is an excess Ach accumulation – Depolarising type of postsynaptic block • Used as a suicidal poison • Causes muscle paralysis and death • Nerve gas (sarin)

51. Myasthenia gravis • Serious neuromuscular disease • Antibodies form against acetylcholine nicotinic postsynaptic receptors at the NMJ • Characteristic pattern of progressively reduced muscle strength with repeated use of the muscle and recovery of muscle strength following a period of rest • Present with ptosis, fatiguability, speech difficulty, respiratory difficulty • Treated with cholinesterase inhibitors

52. Muscle contraction • Depolarisation of the muscle membrane spreads through the muscle • Causes muscle contraction • Excitation - contraction coupling – Excitation : electrical event – Contraction : mechanical event

53. Mechanism of Ca release • AP spreads through t tubule into the muscle tissue • Close to the sarcoplasmic reticulum, AP activates dihydropyridine DHP receptor (dihydropyridine blocks these Ca channels) located in the T tubule • DHP receptor is physically close to a Ryanodine receptor located on the sarcaplasmic reticulum • Releases Ca from sarcoplasmic reticulum • Ca flows to the myoplasm in the vicinity of actin & myosin • In cardiac muscle cell – L type Ca channel present in the DHP receptor causes Ca2+ entry from outside – This Ca activates ryanodine receptor – Releases Ca from sarcoplasmic reticulum – calcium induced calcium release occurs • L type Ca channels are blocked by calcium channel blockers used for hypertension • Ryanodine receptors are known to be present in the brain (hippocampus) • Cognitive dysfunction may be related to RyR induced Ca release In Alzheimer’s and PTSD

54. Neuromuscular junction in smooth muscle • There is intrinsic innervation in smooth muscles eg. In GI tract, extrinsic innervation from autonomic nervous system • There is no specialized connection between the nerve fiber and the smooth muscle cell • The nerve fibers essentially passes "close" to the smooth muscle cells and releases the neurotransmitter • The neurotransmitter can bind to any one of the nearby smooth muscle cells • many different neurotransmitters can be released from the many different nerves that innervate smooth muscle cells • They could be excitatory or inhibitory • eg. Ach, norepinephrine, nitric oxide, prostacyclin, endothelin • There is nothing equivalent to the motor endplate in smooth muscle, therefore receptors for the neurotransmitters are located throughout the smooth muscle membrane • Smooth muscle can be made to contract by hormones and paracrine agents

55. Type Neurotransmitter Amines Serotonin (5HT), Dopamine, Norepinephrine, Acetylcholine, Histamine Amino acids Gamma-aminobutyric acid (GABA), Glycine, Glutamate, Aspartate Opioids Beta-endorphin, Enkephalins, Dynorphin, Nociceptin, Kyotorphin Neurokinins Substance P, Neurokinin A, B Endocannabinoids Endocannabinoids (Anandamide, 2AG) Mixed types Nitric oxide and Carbon monoxide (CO) ATP, ADP CART (cocaine and amphetamine regulated transcript) Neuropeptide Y Orexin Other Angiogensin, Calcitonin, Glucagon, Insulin, Leptin, Atrial natriuretic factor, Estrogens, Androgens, Progestins, Thyroid hormones, Cortisol. Hypothalamic releasing hormones, Corticotrophin-releasing hormone (CRH), Gonadotropin releasing hormone (GnRH), Luteinizing hormone releasing hormone (LHRH), Somatostatin, Thyrotropin releasing hormone (TRH), Growth hormone releasing hormone (GHRH), Pituitary peptides, Corticotrophin (ACTH), Growth hormone (GH), Lipotrophin, Alpha-melanocyte-stimulating hormone(alpha-MSH), Oxytocin, Vasopressin, Thyroid stimulating hormone (TSH), Prolactin, Gut hormones Cholecystokinin (CCK), Gastrin, Motilin, Pacreatic polypeptide, Secr etin, Vasoactive intestinalpeptide (VIP), Bombesin, Bradykinin, Carnosine, Calcitonin G related peptide, Delta sleep factor, Galanin, Focretin, Melanocyte concentration hormone NEUROTRANSMITTERS 56

56. Glutamate – The most abundant and the main excitatory neurotransmitter in the brain – Responsible for 75% excitatory neurotransmission in the CNS – Ca2+ is necessary for release – Reuptake to the presynaptic terminal by glutamate transporter or via glial cells – receptors • Ionotropic receptors: AMPA (Na+), Kainate (Na+), NMDA (Ca2+ and Na+) • NMDA receptor is normally blocked by Mg2+ • When glutamate binds to AMPA receptors, Na channel open up, Na influx occurs, membrane is depolarised, depolarisation removes Mg2+, then glutamate and glycine binding to NMDA receptor will open up Na+ and Ca2+ channels, Ca2+ influx, activates protein kinases and several actions • Metabotropic glutamate receptors: second messenger system, act thru inositol phosphate and cAMP, present in presynaptic and postsynaptic – Increased levels of glutamate causes neuronal excitotoxicity, known to be involved in Alzheimer’s disease, NMDA antagonists are used as a treatment – Aspartate is an agonist – NMDA receptor activity is involved in memory processes known as long term potentiation – Glutamate is a mediator of pain impulse pathway, NMDA receptor antagonists are used as pain reducing drugs – present in cortical projection to striatum (basal ganglia). Present in the stretch reflex

57. Acetylcholine (Ach) • First neurotransmitter discovered in 1914 • Secreting neurons are called cholinergic neurons • Secreted at the neuromuscular junction (skeletal muscle contraction), autonomic ganglia (both sympathetic and parasympathetic), parasympathetic postganglionic nerve endings and in central pathways in the basal forebrain and brainstem (memory, arousal, attention, rapid eye movement (REM) sleep • receptors – nicotinic (NN: autonomic ganglia, NM: NMJ) – ionotropic receptors Na+ influx – muscarinic (parasympathetc terminal) » sub types: M1(brain), M2(heart), M3(glands, smooth muscle), M4, M5 » Metabotropic receptors with G protein and second messenger cAMP and K+ channel opening • Agonist: nicotine, muscarine (toad poison) • Inhibitors: NMJ blockers competitive: curare (plant poison), atracurium, depolarising: succinylcholine, botulinum toxin (food poison), organophosphate (insecticide), atropine (muscarinic blocker), neostigmine (AchE inhibitor) • Loss of Ach neurons in Alzheimer’s patients: donepezil (anticholinesterase, increases Ach level) • Pilocarpine (muscarinic chollinergic eye drops used in glaucoma)

58. GABA • Gamma amino butyric acid • The main inhibitory neurotransmitter in the brain • Responsible for 40% inhibitory neurotransmission in the CNS • Present in both presynaptic and postsynaptic inhibition • Reuptake up GABA transporter • receptors – GABA A receptor (ionotropic): postsynaptic, open up Cl- channel, hyperpolarisation, inhibition, alcohol, antiepieptics (barbirurates), benzodiazepine (diazepam), activate these receptors – GABA B receptor (metabotropic): presynaptic , G protein coupled action, increase K+ efflux, inhibit Ca2+ influx through presynaptic Ca2+ channels – GABA C receptor is also known to be present • Increased GABA activity causes sedative effect • Main neurotransmitter which produces sleep • GABA decreases serotonergic, noradrenergic, cholinergic and histaminergic neuronal activity to cause Non-REM (rapid eye movement) sleep

59. GABA • Secreted by the neurons originating in striatum terminating in globus pallidus & substantia nigra • faulty GABAergic neurotransmission has been implicated in a broad range of neuropsychiatric disorders including anxiety disorders, schizophrenia, alcohol dependence, and seizure disorders • Endogenous GABA binds to GABA-a receptors in the basolateral amygdala and inhibits anxiety responses • Alterations in GABAergic transmission can result in severe disturbances in brain activity and a deficit in GABAergic transmission can lead to epileptogenesis. • Some metabolic alterations in GABA levels in the brain occur coincidentally with some degenerative brain diseases, Huntington’s chorea and Parkinsonism • GABA transport inhibitors, competitive inhibition of GABA and substrate inhibitor of GABA are used to treat epilepsy

60. Glycine • An inhibitory neurotransmitter in the spinal cord • It is also known to be present in retina • Co-activates NMDA receptor with gulutamate • It has ionotropic receptor: Activate Cl- channels and cause hyperpolarisation • Action of glycine is antagonised by strychnine • Strychnine poisoning causes muscle spasms, convulsions and muscle hyperactivity • Reuptake by transporter • Parallel circuits potentiate GABA inhibition

61. Norepinephrine & epinephrine • present in the autonomic nerves, brain stem, hypothalamus, locus ceruleus of the pons • Reuptake by transporter • Metabolised by MAO (monoamine oxidase); MAO inhibitors are used as antidepressants • Increases BP and HR • Control the overall activity of the brain and the mood • Excitatory or inhibitory depending on the receptor • Receptors – α1A, α1B, α1D, α2A, α2B, α2C, 1, 2, 3 • Metabotropic receptors G protein coupled, second messenger: cAMP or Ca2+ and protein kinase – with norepinephrine having a greater affinity for α-adrenoceptors and epinephrine for β-adrenoceptors • Locus ceruleus is the principal site of norepinephrine in the brain, involved in arousal, stress reaction, attention, sleep-wake cycle • In antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs) are used by blocking transporters

62. Dopamine • Dopamine (DA) is present in several important areas and pathways in the brain involved in reward pathway – Ventral tegmental area (VTA) of the midbrain – Nucleus accumbens (NA) of basal forebrain (brain pleasure centre) – Mesocortical pathway from midbrain to prefrontal cortex – Mesolimbic pathway from midbrain to limbic system – Nigrostriatal pathway from substantia nigra to striatum in the limbic system • Involved in motor control, dopamine levels are low in Parkinson disease • Involved in reward behavior and addiction and in psychiatric disorders such as schizophrenia • Receptors (metabotropic) – D1, D2, D3, D4 D5 – D1-like (D1 and D5) increases cAMP and D2-like (D2, D3 and D4) decreases cAMP – Overstimulation of D2 receptors may lead to schizophrenia • Autoreceptors are present, Reuptake by dopamine transporter , MAO degrade dopamine • Drug addiction is due to increased dopamine levels – Cocaine and methamphetamine act by inhibiting dopamine transporters and thereby increasing dopamine level in the brain to a unimaginably high levels , – Opioids and heroin act directly on DA neurons or inhibit GABA inhibition of DA neurons – Cannabis and marijuana activate endocannabinoids which act presynaptically , inhibit GABA, increases DA levels – Nicotine: More complex mechanism increasing DA • Most drugs of addiction blocks the transporters and thereby increases DA levels to a very high levels causing euphoria and “high” but persistent drug use with addiction causes tolerance and dependence and subsequent damage to the brain

63. • Nigrostriatal dopamine pathway: – From substantia nigra to striatum, is part of the extrapyramidal nervous system and controls motor function and movement. • Mesolimbic dopamine pathway – From midbrain ventral tegmental area to the nucleus accumbens in the ventral striatum, a part of the limbic system of the brain thought to be involved in many behaviours such as pleasurable sensations and motivation, the powerful euphoria of drugs of abuse, as well as delusions and hallucinations (positive symptoms) of psychosis. • Mesocortical dopamine pathway: – From midbrain ventral tegmental area and sends its axons to areas of the prefrontal cortex, where they may have a role in mediating cognitive symptoms and executive function (dorsolateral prefrontal cortex) and affective symptoms (ventromedial prefrontal cortex) of schizophrenia. • Tuberoinfundibular dopamine pathway – From hypothalamus to anterior pituitary gland and controls prolactin secretion.

64. Serotonin • Chemically: 5Hydroxy tryptamine (5HT) • present in high concentration in platelets and in the GIT, within the brain stem in the midline raphé nuclei, which project to a wide area of the CNS including the hypothalamus, limbic system, neocortex, cerebellum and spinal cord • After secretion, reuptake by serotonin transporter (SERT) • Once inside the presynaptic terminal it is metabolised by MAO • Receptors – Metabotropic : 5HT1 (A,B,D,E,F), 5HT2 (A,B,C), 5HT4, 5HT5 (A,B), 5HT6, 5HT7 – Ionotropic : 5HT3 • Regulate arousal, mood and social behavior, appetite and digestion, sleep, memory, and sexual desire • Low levels are known to be involved in depression • Selective serotonin reuptake inhibitors (SSRI) blocks serotonin transporter and increases serotonin levels or SNRI (Serotonin Norepinephrine reuptake inhibitors) are also used • Serotonin is involved in migraine (serotonin agonists are used) • Serotonin antagonists are used for vomiting • Tricyclic antidepressants (TCAs) inhibit the reuptake of norepinephrine serotonin • Monoamine oxidase (MAO) metabolises 5HT.MAO inhibitors are used as antidepresants • 5HT1A acts as autoreceptor • 5HT1 B,D,F receptors are stimulated by antimigraine drug sumatriptan • 5-HT2A receptor has been implicated in the cognitive process of working memory. Useful in schizophrenia • 5-HT 2C receptor stimulation produce anxiogenic and anorectic effects from interactions with the hypothalamic melanocortin and leptin pathways • 5HT3 antagonist act as strong antiemetic agent (Ondansetron) • 5-HT4 receptors modulate the release of acetylcholine and dopamine and implicated in cognition and anxiety. • Increasing the levels of serotonin in the brain can alleviate OCD symptoms

65. Serotonin • Selective-serotonin reuptake inhibitors (SSRIs) – used to treat depression 66

66. Cocaine acts as a monoamine agonist by blocking the reuptake transporter enzyme

67. Opioid Peptides • Peptides originally known to be similar to morphine • Different types of –  Endorphin: present in pituitary, earliest discovered opioid peptide – enkephalins: met-enkephalin, leu-enkephalin: present at substantia gelatinosa in the spinal cord & brain stem reticular nuclei, widely distributed – Dynorphin: recently discovered • Opioid peptides are involved in the descending pain inhibitory pathway • Nociceptin – Similar to dynorphin A, bind to nociceptin receotor • Kyotorphin – it acts by releasing an met-enkephalin, lower in patients with persistent pain, is a neuromodulator • receptors: , , : metabotropic, GPCR • Activation of μ receptors increases K+ conductance, hyperpolarizing central neurons and primary afferents. Activation of κ receptors and δ receptors closes Ca2+ channels • Opioid act on the brainstem and inhibit GABA inhibition on spinal cord pain inhibitory action or directly act on spinal cord • Presynaptic or postsynaptic inhibition occurs • Opioid system is involved in pain modulation, stress, appetite regulation, learning, memory, motor activity, immune function • Opioids addiction is due to their action through reward pathway (VTA etc) and dopamine •

68. Histamine • present in pathways from hypothalamus to cortical areas & spinal cord • receptors: H1, H2, H3 (all present in brain) • functions related to arousal, sexual behaviour, drinking, pain • H1 receptors: • Apart from periphery these receptors are distributed in the thalamus, cortex, and cerebellum. H1 receptor is the mediator of allergy, sedation and weight gain produced by a number of antipsychotic and antidepressant drugs. • H2 receptors: • Apart from periphery, H2 receptors are widely expressed in the neocortex, hippocampus, amygdala, and striatum and produces excitatory effects in neurons of the hippocampal formation and thalamus. Several studies indicates that the stimulation of these receptors produces antinociceptive effects. • H3 receptors: • These are located presynaptically on axon terminals. Those located on histaminergic terminals act as autoreceptors. In addition, H3 receptors are located on nonhistaminergic nerve terminals, where they act as heteroreceptors to inhibit the release of a variety of neurotransmitters - including norepinephrine, dopamine,acetylcholine, and serotonin. Particularly high levels of H3 receptor binding are found in the frontal cortex, striatum,amygdaloid complex, and substantia nigra. Antagonists of H3 receptors have been proposed to have appetite suppressant,arousing, and cognitive-enhancing properties. • H4 receptors: • It has identified recently and is detected predominantly in the periphery, in regions such as the spleen, bone marrow, and leukocytes.

69. Neurokinins • Substance P • found in primary nerve ending in the spinal cord • mediator of pain in the spinal cord • Present in intestine, various peripheral nerves and many parts of the CNS • Neurokinin A and neurokinin B are similar to Sub P • Receptors: Neurokinin NK1, NK2 and NK3: metabotropic receptor

70. Nitric oxide (NO) • is a neurotransmitter in the central, peripheral, and enteric nervous systems • Inhibitory (smooth muscle relaxation) • It has a role in a variety of neuronal functions including learning and memory processes, cortical arousal, nociception, food intake, penile erection, yawning, blood vessel dilatation and immune response • Neurons synthesize NO as a response to the activation of N-methyl- D-aspartate (NMDA) receptors by the excitatory amino acid glutamate • NO is generated in the neuronal cells by the enzyme nitric oxide synthase (NOS) with calcium and calmodulin as cofactors • NO has been described as an unconventional neurotransmitter, because it is not stored in synaptic vesicles and not released upon membrane depolarization but released as soon it is synthesized

71. Endocannabinoids • The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system (CNS) development, synaptic plasticity, and the response to endogenous and environmental insults. • The ECS is comprised of cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids • The most abundant cannabinoid receptor is the CB1 cannabinoid receptors, however CB2 cannabinoid receptors • Exogenous cannabinoids, such as tetrahydrocannabinol (Cannabis), produce their biological effects through their interactions with cannabinoid receptors. • 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide) are the best-studied endogenous cannabinoids.

72. • CGRP (Calcitonin gene related peptide): – Present in the pain pathway – Involved in migraine – Monoclonal antibodies against CGRP useful in migraine • ATP – Present in ANS – Binds to P2X receptors, which are ligand-gated ion channel receptors – Present in dorsal horn, may be involved in pain pathway • CART (cocaine and amphetamine regulated transcript) – hypothalamus and midbrain enriched neurotransmitter with an antioxidant property – can be found in mitochondria, which is the main source of reactive oxygen species – Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in PD – It is a potential neurotrophic factor and is involved in the regulation of hypothalamic-pituitary-adrenal axis and stress response as well as in energy homeostasis. CART is also highly expressed in limbic system – Possess antidepressant properties • Neuropeptide Y – influences many physiological processes, including cortical excitability, stress response, food intake, circadian rhythms, and cardiovascular function – increases eating and promotes obesity – Neuropeptide Y inhibits orexin – Leptin inhibits neuropeptide Y • Orexin (hypocretin) – Involved in arousal, wakefulness, and appetite – Narcolepsy is caused by a lack of orexin in the brain due to the destruction of the cells that produce it

73. Neuromodulators • Neurotransmitters transmit an impulse from one neuron to another • Neuromodulator modulate regions or circuits of the brain • They affect a group of neurons, causing a modulation of that group • Neuromodulators alter neuronal activity by amplifying or dampening synaptic activity – eg. dopamine, serotonin, acetylcholine, histamine, glutamate

74. Channelopathies • In excitable cells – periodic paralysis (K + channel, Na + channel) – myasthenia (nicotinic Ach receptor with a ligand Na channel) – myotonia (K + channel) – malignant hypothermia (Ryanodine Receptor, a Ca 2+ channel), – long QT syndrome (Na + and K + channel) • In nonexcitable cells – cystic fibrosis (Cl - channel) – Bartter’s syndrome (K + channel)

Psych Electrophysiology 2020 final

You are reading a preview.

Check these out next

Psych Electrophysiology 2020 final

More Related Content

Slideshows for you (20)

Similar to Psych Electrophysiology 2020 final (20)

More from vajira54 (20)

Recently uploaded (20)

Psych Electrophysiology 2020 final