45 Neurochemistry October 25, 2013 Chapter 12: Dr. Diane M. Jaworski

46 What diseases are associated with the neurotransmitters? What are the major neurotransmitters? What is the function of the neurotransmitters? How do neurotransmitters work?

47 © Squire et al., Fundamental Neuroscience, 2 nd ed How do neurotransmitters work? Life Cycle of a Neurotransmitter Synthesized in the neuron - peptides made in cell body - others assembled in button Stored in vesicles Released by calcium- mediated exocytosis Activation of receptor on postsynaptic cell by sodium ion Removal from synaptic cleft, taken up by: glial cell, pre-synaptic neuron, or degraded in synaptic cleft

48 How do neurotransmitters work? © Kandel et al. Principles of Neuroscience 2000 Binding to receptor opens the ion channel and initiates an action potential directly Binding to receptor releases a second messenger that causes channel opening and action potential indirectly

49 What are the major neurotransmitters in the CNS? 3. Small Molecule Neurotransmitter Acetylcholine Excitatory amino acids - Glutamate - Aspartate Inhibitory amino acis - GABA - Glycine Catecholamines - Dopamine - Norepinephrine (noradrenaline) - Epinephrine (adrenaline) Serotonin 1. Neuropeptides Substance P Opioid peptide 2. Gaseous Neurotransmitter Nitric Oxide

50 Acetylcholine Synthesized from: dietary choline and acetyl-CoA from Krebs cycle Degraded in synaptic cleft by the enzyme Acetylcholinesterase (AChE) Can treat neurological disorders of ACh using AChE inhibitors – keeps ACh in cleft longer Foods high in choline: eggs, meats, beans (lentils, soybeans), leafy green veges (collard greens, swiss chard, kale) © Siegal & Saprli Essential Neuroscience 2006

51 Acetylcholine autonomic ganglionic neurons involved in visceral functions The most widespread neurotransmitter in the nervous system © Tottora & Grabowski Principles of Anatomy & Physiology 1996

52 Acetylcholine - motor neurons of spinal cord to innervate muscle of body - motor neurons of cranial nerves to innervate muscles of head/neck What happens if ACh release decreases or receptors are blocked? © Tottora & Grabowski Principles of Anatomy & Physiology 1996

53 Myasthenia gravis - Autoimmune disorder, antibodies block AChR - muscle weakness - treat with AChE inhibitors to keep ACh in synapse longer

54 Acetylcholine AChR blockers cause paralysis Some are irreversible!!!! - Atropine (belladonna plant) - Curare (plant dart poison) -  -bungarotoxin (snake venom, Fig A) - Conotoxin (snail, Fig B) © Bear et al.Neuroscience 1996 © Purves et al. Neuroscience 2008

55 Acetylcholine -many CNS synapses -involved in regulating alertness/attention, sleep, learning/memory © Nestler et al. Molecular Neuropharmacology, 2001 Neurons die in Alzheimer’s disease

56 Alzheimer’s disease - neurofibrillary tangle-intracellular  -amyloid plaques-extracellular - treat with AChE inhibitors

57 Progression of Alzheimer’s Disease measured by decreased glucose utilization in brain Note loss of nucleus basalis of Meynert (stars) that leads to decreased activity in cerebral cortex (arrows) **

58 Alzheimer’s disease -cortical wasting due to death of acetylcholine neurons -memory loss: factual information is lost first with time, procedural memory is lost Normal Alzheimer’s

59 Tower of Hanoi See how you do:

60 Glutamate is the most common neurotransmitter in the brain Increases action potential firing probability Increased release induces epilepsy Up-take by glia or in presynaptic neuron Excitatory Amino Acids © Siegal & Saprli Essential Neuroscience 2006 Glutamat e (and Aspartate)

61 Glutamate and neurotoxicity Amyotrophic Lateral Sclerosis (ALS) Lou Gehrig’s disease Motor neurons preferentially die No definitive cause known

62 made from Glutamate!! Decreases action potential firing probability Up-take by glia or in presynaptic neuron GABA (and Glycine) Inhibitory Amino Acids GABA (and Glycine) © Siegal & Saprli Essential Neuroscience 2006

63 GABA © Purves et al. Neuroscience Benzodiazepine (valium) - Barbiturates - alcohol Adds to GABA inhibition Used for sedation, anesthesia, anti-anxiety

64 Glycine Inhibitory Amino Acid Glycine Strychnine (rat poison) blocks glycine binding to its receptors - induces seizures © Purves et al. Neuroscience 2008

65 Catecholamines Degraded: - intracellularly within neurons or up-take by glia Tyrosine L-DOPA dopamine norepinephrine epinephrine © Siegal & Saprli Essential Neuroscience 2006

66 - Substantia nigra is main source of dopamine - Death of brainstem substantia nigra neurons in Parkinson’s disease - Increased dopamine involved in schizophrenia Dopamine © Purves et al. Neuroscience 2008

67 Norepinephrine/Noradrenaline - Locus Coeruleus is main source of norepinephrine (NE) - Involved in depression (decreased NE) & mania (increased NE) © Purves et al. Neuroscience 2008

68 Epinephrine/Adrenaline - Role of epinephrine in CNS not well characterized -In PNS, adrenaline plays a role in autonomic/sympathetic NS “Fight or flight” stress responses © Purves et al. Neuroscience 2008

69 - Brainstem raphe nuclei are main source of serotonin - Involved in: pain inhibition, sleep, depression Serotonin (5-HT) © Purves et al. Neuroscience 2008

70 Symptoms of Major Depression Patients must show one of the following: - Depressed mood most of the day - Diminished interest or pleasure in activities most of the day Other Symptoms: - Large increase or decrease in appetite - Insomnia or excessive sleeping - Restlessness or slowness of movement -Fatigue or loss of energy -Indecisiveness or diminished ability to think or concentrate - Feelings of worthlessness or excessive guilt - Recurrent thoughts of death or of suicide

71 Understanding Depression Regardless of the initial triggers, the final common pathways to depression involve biochemical changes in the brain Altered neurotransmitters or hormones Current drug therapies target these biochemical changes

72 Peptide Neurotransmitters Substance P -conveys pain from the periphery © Kandel et al.Principles of Neuroscience 2000

73 Peptide Neurotransmitters Endogenous opioids (e.g., endorphins) Caffeine stimulates endorphin release

74 Endocannabinoids

75 Endocannabinoids

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