Neurotransmitters

1. Neurotransmitters Topic 2

2. Acetylcholine • The first neurotransmitter to be identified — about 80 years ago • Released by neurons connected to • voluntary muscles, causing them to contract • by neurons that control the heartbeat. • AChis also a transmitter in many regions of the brain (less is known about these).

3. Acetylcholine • Synthesized in axon terminals. • When an action potential arrives at the nerve terminal, electrically charged calcium ions rush in, and ACh is released into the synapse, where it attaches to ACh receptors on the target cells.

5. Ach Effects • On voluntary muscles (Motor division of Somatic NS), opens sodium channels and causes muscles to ____________. • In cardiac tissue acetylcholine neurotransmission has an inhibitory effect, which ___________ heart rate. • Acetylcholine also behaves as an excitatory neurotransmitter at neuromuscular junctions in skeletal muscle, but inhibitory in cardiac muscle. How is this possible? contract lowers http://sites.sinauer.com/neuroscience5e/animations06.01.html

6. Ach: Breaking it down acetylcholinesterase • ACh is then broken down by the enzyme __________________ and resynthesized in the nerve terminal.

7. Question • What would happen if some of the receptors for ACh were blocked?

8. Myasthenia Gravis • Antibodies that block one type of ACh receptor cause myasthenia gravis, a disease characterized by fatigue and muscle weakness.

9. Ach contd. • Less is known about Acetylcholine in the brain. • Recent discoveries suggest that it may be critical for normal attention, memory, and sleep. • Because ACh-releasing neurons die in Alzheimer’s patients, finding ways to restore this neurotransmitter is a goal of current research. • Drugs that inhibitacetylcholinesterase — and increaseACh in the brain — are presently the main drugs used to treat Alzheimer’s disease

10. Questions • 1st NT discovered was? • What causes Masthenia Gravis? What are its symptoms? • What functions are ACh associated with in the brain? • How is ACh related to Alzheimer’s? Currently, the main drugs used in Alzheimer’s treatment inhibit___. • What is the effect of ACh on somatic muscle? • What is the effect of ACh on cardiac muscle?

11. Amino acids What do you know about Amino Acids?

12. Name the two major inhibitory Neurotransmitters? Amino Acids • Monomers of Proteins • A.A. such as Glycine and gamma-aminobutyric acid (GABA) inhibit the firing of neurons. Glycine GABA

13. If Glycine or GABA were to bind to receptors on a dendrite, what would you expect the cellular response to be?

14. In vertebrates, GABA acts at inhibitory synapses in the brain by binding to specificmembranereceptors • This binding causes the opening of ion channels to allow the flow of either (-) charged chloride ions into the cell or (+) charged potassium ions out of the cell. • This action results in a (-) change in themembranepotential, usually causinghyperpolarization. • 2 general classes of GABA receptor: • GABAA: a ligand-gated ion channel • GABAB: metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).

16. Questions • How do GPCR mediated actions work? • What is the role of GABA and Glycine. • If GABA is used to regulate overstimulation of motor control, what could be the consequence of destroying GABA neurons?

17. Amino Acid NT: GABA • Gamma-aminobutyric Acid • Not used to make proteins • Inhibitory • Activity increased by ______________(Valium) and anticonvulsant drugs. • ____________ disease is a hereditary disorder that begins during midlife often characterized by uncontrollable movements. benzodiazepines Huntington’s

18. Amino Acid NT: GABA & Huntington’s • Huntington’s disease is a hereditary disorder (dominant) that begins during midlife often characterized by uncontrollable movements. • How could GABA be related to Huntington's? • The GABA producing neurons in brain centers that coordinate movement degenerate. • Loss of inhibitory NT

19. Huntington’s Effects • The basal ganglia is a small system in the middle of the brain that has a lot of control over movement. • The main parts of the basal ganglia include: the • caudate • putamen • Globuspallidus • substantianigra • and the subthalamus

20. Huntington’s Damage • The globuspallidusis divided into two parts, interna (GPi) and externa (GPe). • Eventually, HD knocks out many neurons throughout the basal ganglia, but it apparently starts with the inhibitory GABA neurons projecting to the Gpe from the putamen.

21. PUTAMEN

22. DESTROYED PUTAMEN GABA E GlobulusPallidus Motor Control GABA GABA Subthamlic nucleus Glutamate IGlobulusPallidus

23. Huntington’s Damage • The putamen's inhibitory GABA neurons which project to the GPe are destroyed. • This allows the inhibitory GABA neurons from the GPe to the subthalamus to fire. • The subthalamus'excitatoryglutamate neurons to the GPiare thus inhibited. • The GPihas inhibitory GABA neurons projecting to the thalamus and the brainstem which would normally inhibit motion (but it is never activated). • In this case, the neuron activating these inhibitory neurons is, itself, inhibited, so the thalamus and brainstem are disinhibited, causing random, frequent motion.

24. Huntington’s Damage • Putamen’s GABA inhibits Globus Pallidus(but this is destroyed)-normally fires to the GPe • Externa’sGABA which would have been inhibited, now fires, inhibiting the subthalamus’ glutamate (excitatory) from firing. • These GlutamateNTs were necessary to turn on the Globus PallidusInterna’s GABA, which is supposed to inhibit motion at the thalamus & brainstem.

26. What drugs can increase the activity of GABA?

27. Review • 1st NT discovered was? • What causes Masthenia Gravis? What are its symptoms? • What functions are ACh associated with in the brain? • How is ACh related to Alzheimer’s? Currently, the main drugs used in Alzheimer’s treatment inhibit___. • What is the effect of ACh on somatic muscle? • What is the effect of ACh on cardiac muscle? • Name two amino acid inhibitory neurotransmitters? • How would one expect an inhibitory NT to affect the membrane potential of a neuron? • How do GPCR mediated actions work? • If GABA is used to regulate overstimulation of motor control, what could be the consequence of destroying GABA neurons? • What drugs can increase the activity of GABA?

28. Amino Acid NTs: Glutamate & Asparate • Glutamate & Asparate are excitatory NTs. • Example: Activate N-methyl-d-asparate (NMDA) receptors. • In developing animals, NMDA receptors seem involved in activities ranging from learning and memory to development and specification of nerve contacts. • Stimulation of NMDA receptors may have beneficial changes in the brain. • Overstimulation may lead to cell damage & death (as happens during stroke)

29. Glutamate

31. Why Strokes are Bad • Lack of oxygen causes the neuron's normal process for making ATP for energy to fail. • The cell switches to anaerobic metabolism, producing lactic acid. • ATP-reliant ion transport pumps fail, causing the cell to become depolarized, allowing ions, including calcium (Ca++), to flow into the cell. • The ion pumps can no longer transport calcium out of the cell, and intracellular calcium levels get too high. • The presence of calcium triggers the release of the excitatoryaminoacidneurotransmitterglutamate. • Glutamate stimulates AMPA receptors and Ca++-permeable NMDA receptors, which open to allow more calcium into cells.

32. Why Strokes are Bad • Excess calcium entry overexcitescells and causes the generation of harmful chemicals like free radicals, reactive oxygen species and calcium-dependent enzymes such as calpain, endonucleases,ATPases, and phospholipases in a process called excitotoxicity.  Calcium can also cause the release of more glutamate. • As the cell's membrane is brokendown by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell. • Mitochondriabreakdown, releasingtoxins and apoptoticfactors into the cell. • The caspase-dependentapoptosiscascade is initiated, causing cells to "commit suicide." • If the cell dies through necrosis, it releases glutamate and toxic chemicals into the environment around it. Toxins poison nearby neurons, and glutamate can overexcite them.

34. What was that? • What do you need to know? • NMDA receptors are important for learning. • NMDA receptors can be over stimulated, leading to too much intracellular calcium, which can act as a 2nd messenger to trigger Apoptosis

35. Glutamate/Asparate • Developing drugs that block or stimulate activity at NMDA receptors holds promise for improving brain function and treating neurological and psychiatric disorders.

36. Catecholamines • A class of biogenic amines called Catecholamines include Dopamine and norepinephrine • Found in Peripheral Nervous System (PNS) & Brain

37. Catecholamines: Dopamine • Type: both excitatory and inhibitory • Location: brain and peripheralnervoussystem • Function 1: control movement • Function 2: Cognition and emotions • Function 3: regulate hormone responses (endocrine system)

38. Catecholamines: Dopamine • Dopamine helps to regulate Movement: • Dopamine linked to disease • A dopamine deficit in Parkinson’s patients • Muscle tremors • Rigidity • Difficulty moving • Treatment uses Levodopa • Dopamine is synthesized from levodopa

39. Catecholamines: Dopamine • Dopamine: Involved in Cognition & Emotion • Abnormalities associated with Schizophrenia • Drugs that block dopamine receptors are often used to treat psychotic symptoms. But if we block dopamine receptors, what may be an unintended consequence?

40. Catecholamines: Dopamine • Dopamine Regulates the Endocrine System • Directs the hypothalamus to manufacture hormones & hold them in the pituitary gland for release into the bloodstream, or to triggerthe release of hormones held within cells in the pituitary.

41. Catecholamines: Dopamine • Dopamine plays a major role in the brain system that is responsible for reward-driven learning. • Every type of reward that has been studied increases the level of dopamine transmission in the brain, and a variety of highly addictive drugs, including stimulants such as cocaine and methamphetamine, act directly on the dopamine system.

42. Catecholamines: Norepinephrine • Norepinephrine: • May play a role in learning & memory • Deficiencies occur in patients with Alzheimer’s Disease, Parkinson’s disease, & Korsakoff’s syndrome (associated with chronic alcoholism) • All lead to memory loss & decreased cognitive function. • Sympathetic release throughout the body regulates heart rate & blood pressure. • Acute stress increases release from sympatheticnerves and the adrenal medulla

43. Review Dopamine is a member of a class of NTs called __________________ Catecholamines Korsakov's syndrome is associated with a deficiency in __________________ norepinephrine • Sympathetic release (of the above NT) throughout the body regulates __________________ & __________________ Heart rate blood pressure

44. Serotonin • Present in the brain and other tissues. • In the brain, important factor in • sleep quality, • mood, • depression, • and anxiety. • Most receptors are G protein coupled receptors

45. Serotonin-Pharmacology • May be manipulated by analogs, chemicals with molecular structures similar to that of serotonin. • Drugs that alterserotonin’saction, such as Prozac (fluoxetine), relieve symptoms of depression and obsessive-compulsive disorder.

46. Serotonin-Pharmacology • Prozac and other recent drugs help people with depression by preventing the neurons from "vacuuming" up excess serotonin, so that there is more left floating around in the synapses.  • Warm milk before bedtime also increases the levels of serotonin and can help you sleep.  • Serotoninis a derivative of tryptophan, which is found in milk

47. Serotin plays an important role in • ___________________ • ___________________ • ___________________ • ___________________ Sleep quality mood depression anxiety

48. 4.) Serotonin • Type: excitatory • Location: brain, blood platelets, and lining of the digestive tract • Function: involved with emotional states • Disease: ObsessiveCompulsiveDisorder (OCD), Depression • Treatment: Prozac (fluoxetine)

49. Questions • Valium is used to treat seizure and convulsion by affecting which neurotransmitter? • L-dopa is to Parkinson`s disease as Prozac is to? GABA OCD

50. What are peptides? • Short chains of amino acids