Lecture 1. Aug 26 2024 History and Neuro Review CLASS NOTES (1)

Pharmacology: Drugs, Brain, Behavior Lake Forest College BIOL, PSYCH, BMB, NEUR372: Fall 2024 WELCOME!!! 1 Get out your cell phones or laptops Text: “stevem150” at 22333 Web: pollev.com/stevem150...

Pharmacology: Drugs, Brain, Behavior Lake Forest College BIOL, PSYCH, BMB, NEUR372: Fall 2024 WELCOME!!! 1 Get out your cell phones or laptops Text: “stevem150” at 22333 Web: pollev.com/stevem150 2 Z 3  Dendrites - Receivers of The Neuron information from other - processing neurons - transmitting Soma: - Cell body, core of neuron function/energy/life Terminal Button Axon – carrier of Terminal Button – electrical information release of from one end of neuron neurotransmitters to the other (wire) 4  Axoplasmic transport Active process that moves proteins and other matter along microtubule tracks Anterograde direction: soma to terminal buttons Retrograde direction: terminal buttons to soma Kinesin attaches to the “to be transported” anterograde item and moves it down the microtubules Dynein attaches to the “to be transported” retrograde item and moves it up the microtubules 5  Neuron membrane Phospholipid bilayer - Separates outside from inside of neurons - Prevents free passage of molecules (unless lipid soluble) - Inserted into the bilayer are other proteins: 1. Receptors 2. Ion channels 3. Transporters 6  Neuron at REST Membrane potential is typically expressed from the inside perspective - at rest, the membrane potential sits at approximately -70 mV - based on ion charge: the inside and outside are polar opposites = the neuron is polarized OUTSIDE Key ions -70 mV - Proteins (A-) - Sodium (Na+) INSIDE - Chloride (Cl-) - Potassium (K+) - Calcium (Ca2+) 7  Neuron at REST Inside of neuron is negatively charged relative to the outside (membrane potential) - primarily because of negatively charged proteins (A-) - low levels of Cl- and Na+ relative to the outside - high levels of K+ relative to the outside, but does not overcome the (-) charge due to the proteins A - K+ Cl- Na+ 8  Neuron at REST Outside of neuron is positively charged relative to the inside (membrane potential) - primarily because of Na+ ions - higher levels of Cl- relative to the inside - low levels of K+ relative to the inside K+ Cl- Na + A - K+ Cl- Na+ 9  Neuron at REST Sodium-Potassium pump is an active transporter moving Na+ and K+ across the membrane - keeps the balance of Na+ outside of the neuron - moves 3 Na+ ions outside for every 2 K+ ions brought in - fueled by ATP (uses about 40% of neuron’s energy sources) 10  The Forces that Surround a Neuron Diffusion: pressure to even things out K+ Cl- - pressure to move from high low concentration concentration to Na + - Na+ and Cl- feel the pressure to move inside - K+ feels the pressure to move outside - A- feels the pressure to move outside, but there is no channel or transporter to do so K+ A Cl- - Na+ Stuck inside 11  The Forces that Surround a Neuron K+ Cl- Electrostatic pressure: the pressure of ionic “opposites Na + attract” - pressure to move towards opposite charge - “same” charges repel each other - Na+ and K+ feel the pressure to move inside (more (-) inside) K+ A Cl- - Cl and A feel the pressure to move - - outside (more (+) outside) - Na+ Na+ has a double force (both diffusion and electrostatic) moving it from outside to inside 12  What Happens When Channels are Activated? Action potential: The “spark” to communication At rest, neuron is polarized: -70 mV Na+ permeable channel is activated (e.g., TRPV1) Forces push Na+ inside The inside is not so negative (less polarized) -55 to –50 mV are “magical” voltages - 55 to -50 mV represents the threshold for an action potential When enough Na+ flows inside to hit –55 mV other channels open - Voltage dependent Na+ channels open - rush of Na+ comes in and triggers an ACTION POTENTIAL 13  What Happens When Channels are Activated? Action potential: Neuron is no longer at rest The “spark” to communication Electrical charge at that section of the neuron is no longer “polar opposite” (polarized) - this part of the neuron is now “Depolarized” - the inside is now about + 40 mV At the top of the depolarization Na+ channels close - they are refractory/inactivated At (+) voltages, voltage dependent K+ channels open - in this state, both electrostatic & diffusion push K+ out - channels may open prior to peak depolarization This combination of events, & Na+-K+ pump = over-correction - the inside becomes even more negative than at rest - “Hyperpolarized” Voltage dependent K+ channels close bringing the neuron back to resting state 14  How is the Action Potential Propagated? When -55 (-50) mV is hit get the “all-or-none” law to trigger depolarization and the action potential BUT….depolarization only takes place in localized section of neuron In that section of the neuron voltage dependent Na+ channels open The signal may decrease by the time it gets to the next section (decremental conduction), but as long as it stays above -55 mV the process repeats (all-or-none depolarization; action potential) Domino effect 15 “Ya, I know that” Quiz... 16 X “Ya, I know that” Quiz... What type of ion channel opens to initiate an action potential and which opens up to repolarize the neuron? Answer C 17  How is the Action Potential Propagated? Most neurons are covered by a myelin sheath - produced by oligodendrocytes (CNS) or Schwan cells (PNS) - protects the neuron Only place where ions can be exchanged is at the “Nodes of Ranvier” - decremental conduction while under the sheath - action potential gets retriggered at each Node of Ranvier - speeder conduction than non-myelinated neurons - process is called Saltatory Conduction - saves on “fuel” Na+-K+ pumps only at nodes Unmyelinated neurons do not “jump propagate” between nodes - less efficient and slower - primarily somatosensory “pain” neurons 18  What’s the Point of the Action Potential? To communicate with other neurons - trigger neurotransmitter release into the synaptic cleft Synapse – place where neurons communicate with each other - neurotransmitters released from one neuron (pre-synaptic neuron) - bind to specific receptors on the other neuron (post-synaptic neuron) - space in-between neurons is the synaptic cleft When the action potential hits the terminal button, Ca2+ channels open - Ca2+ channels are voltage dependent (Cav) - at rest, higher concentration outside of neuron (will flow inside) - like Na+ ions, there is double pressure to move into the neuron Influx of Ca2+ through Cav channels causes fusion of synaptic vesicles (store neurotransmitters) with the membrane - break open, and dump their contents into the synaptic cleft 19 Take Home Messages The neuron is set up with appropriate machinery to be an effective communication relay apparatus - information transfer The neuron is like an electrical wire conducting important information from one end to its other end, setting up a transfer to the next wire 20 What is a drug? “Any chemical entity or mixture of entities, other than those required for the maintenance of normal health (like food), the administration of which alters biological function and possibly structure” – World Health Organization (WHO) 21 22  Ancient Drug Use Ancient philosophies are root of modern medicine - Some of the basic principles of “drugs” for treatment of neurological disorders are still being used Ancient drugs were used for rituals, medicinal purposes, improved capacity/performance, and for recreation - Drugs were typically of plant origin The discovery of “drugs” for treatment of disorders or for recreation was based on: - Trial and error over time and passed on through generations - Watch animals for effect on behaviors  Ancient Pharmacy The pharmacological properties of the plants were known since Homer as shown by the use of plants and herbs in his mythical heroes - his texts included many drugs such as “euphoric” (joyful), “thymophora” (deadly), “salvation” (against sadness), anti- inflammatory and analgesics The Odyssey – 8th century BC “So saying, [Hermes] gave me the herb, drawing it from the ground, and showed me its nature. At the root it was black, but its flower was like milk. Moly the gods call it, and it is hard for mortal men to dig; but with the gods all things are possible.” snowdrop plant protects brain cells from damaging toxins: 24  Plant Based Pharmacy Plant preparations continue to this day, approximately 25% of modern medications are developed from plants - more than 85,000 plant species have been documented for medical use globally Archaeological evidence for use of opium and magic mushrooms – more than 10, 000 years ago 25  Ancient or Modern Pharmacy????? In ancient Greece, olympic victor’s dark ointment (OVDO), mentioned by Galen (c. 129–200 CE), was an opium-based patch applied to the skin of athletes. - dried rapidly and recent measurements indicate a transfer comparable of ~25% of modern transdermal patches (not as potent) In Chaeronea, there was a type of pharmaceutical industry, producing analgesic ointments from flowers of lily, rose, narcissus and iris - Greek/Roman physicians mixed these plants with other common grasses that had no effect on their own, thus introducing the concept of: “the excipient”, a component without pharmacological action that facilitates the intake of the active drug - also knew of “formulation” of their drugs/concoctions: substances would not dissolve in water; therefore, they were often mixed with wine 26  Single Plants or Mixtures for Pain Control Hemlock (poison ingested by Socrates that caused his death) Alcohol Aztec physicians in Central America used chili pepper to treat pain (toothaches) Laudanum (a mixture of alcohol with opioids) Dwale (a combination of bile of a boar, lettuce, vinegar, bryony root, hemlock , opium and henbane) Drugs had variable effectiveness due to: - inconsistent preparation - poor methods of administration - lack of dosing control 27 “Mushrooms” Use of psychedelic mushrooms used in ancient celebrations, religious ceremonies, and to communicate with the gods - Australia (oldest evidence – 10, 000 BCE) - Serbia - Ancient Greece, Rome, Egypt, China - Mayan and Aztec cultures 28  Opium Most widely used drug in ancient history - first cultivated by Sumerians in 3400 BC - ancient users included Romans, Greeks, Indians, Egyptians, Assyrians, Chinese, as well as the Sumerians - opium is derived from the latex in the husk of the poppy flower - used to provide pain relief, induce sleep, cure diarrhea and improve libido Greeks placed importance on the poppy, a “poppy goddess” was celebrated - Homer: “forgetfulness of evil” with ingestion - “plant of joy” 29  Other Interesting Opium Facts Could be purchased from the SEAR S catalogue!! 1.5 million bottles sold annually “A Penyworth of Peace” - Mrs. Winslow Soothing Syrup White Star Secret Liquor Cure (65 mg morphine per ounce + alcohol, cannabis & cocaine) Morpheus Main ingredient of opium called morphine after Greek god of dreams… 30  Cocaine Derived from the coca plant which grows wild in South America For centuries, indigenous people chewed the leaves for their mildly stimulating effect - part of culture for thousands of years - coca-leaf chewing natives could subdue appetite and work longer hours Explorers from Spain arrived in 1500’s; shipping home riches (e.g., minerals, spices, coca leaves) - when leaves shipped to Europe, they lose their potency (so use was originally limited to South America) - 1800s when a method for refining the active ingredients was developed by Albert Niemann (German) allowed transport Angelo Mariani made “Vin Mariani” – mixture of wine and cocaine - adored by elites - Thomas Edison, the Queen of Portugal, the King of Spain, Pope Leo XIII, President William McKinley, sculptor Auguste Rodin, President Ulysses S. Grant - Next Gen, NEW AND IMPROVED: “Elixir Mariani” with 3X cocaine content 31  Cocaine An American John Pemberton, upped the percentage of cocaine – “French Coca Wine” - but the Ku Klux Klan at the time wanted to ban alcohol, so he replaced alcohol with soda water: - the birth of Coca-Cola (new competitors made him up the % again) Health issues were observed, and in 1906 cocaine was removed from “Vin Mariani” and Coca- Cola Cocaine’s addictive qualities were recognized in the 19th century and it became a widely prohibited substance in the early 20th century 32  Who said this? “Why with the time do I not glance aside To new-found methods, and to compounds strange? Why write I still all one, ever the same, And keep invention in a noted weed…” 33 W 34 “Why with the time do I not glance aside To new-found methods, and to compounds strange? Why write I still all one, ever the same, And keep invention in a noted weed…” William Shakespeare (26 April 1564 – 23 April 1616) …and what was he talking about? 35  Cannabis Cannabis has been in use for thousands of years and is believed to have been used in ancient Central and South Asia - a 2,700-year-old grave in western china was found to have 789 grams, or 1.7 pounds of the substance - carbon dating confirmed hemp back to 4000 BC The plant genus Cannabis is a member of the plant family Cannabaceae - 3 primary cannabis species which vary in their biochemical constituents: Cannabis sativa, Cannabis indica, and Cannabis ruderalis - cannabis that has high levels of the psychoactive cannabinoid, delta-9-tetrahydrocannabinol (Δ9-THC), and low levels of the non- psychoactive cannabinoid, cannabidiol (CBD), is referred to as “marijuana” - hemp is defined as a cannabis plant that contains less than 0.3% THC, marijuana is a cannabis plant with more than 0.3% THC - CBD can be derived from both hemp and marijuana plants The leaves and flowering tops of cannabis plants contain at least 489 distinct compounds among 18 different chemical classes 36  Cannabis Even the Founding Fathers of the United States grew hemp - George Washington (and Thomas Jefferson) grew cannabis on his plantation for about 30 years - G.W. records indicate he was interested in its medical properties (cultivated it to increase the potency of his crop) Early 19th century Irish physician William O’Shaughnessy went to India to study its use (came back with a large supply ) to treat rheumatism, tetanus, cholera, pain, muscle relaxant, migraine, epilepsy In 1915, father of modern medicine, Sir William Osler, advocated for cannabis use in migraine, “Cannabis indica is probably the most satisfactory remedy” Wasn’t until 20th century that it fell out of favor… 37  Cannabis and Politics Medicinal cannabis was derailed by political factors in the United States - propaganda that it was a drug of abuse used by minority and low-income communities - Federal Bureau of Narcotics (1930s) associated psychosis, mental deterioration, addiction, and violent crimes to marijuana use - some historians believe it was to reduce the size of the growing hemp industry by prominent businesses (nylon was coming on age) - led to the Marihuana Tax Act of 1937 (opposed by American Medical Association) - imposing heavy tax/fines on any use of cannabis - Journal of the American Medical Association, still recommended oral preparations of cannabis for migraine - stigmatized in 1960’s with “psychedelic hippie counterculture” - 1970 marijuana classified as a Schedule 1 substance (same as heroin and lysergic acid diethylamide (LSD)) - the consequence of the Schedule 1 classification has been detrimental to researching its benefits (NO MEDICINAL BENEFIT) - despite the insistence of the Schedule 1 classification, Department of Health and Human Services, in 2001 filed Illinois legalizes cannabis: 2020 a patent for “cannabinoids as antioxidants and neuroprotectants” - also contradiction to the Schedule 1 status, Federal Drug Administration (FDA) approved synthetic versions of the cannabinoid Δ9-THC for medicinal purposes. (recognized by the government to be therapeutic) - multiple medical societies in the last 2 decades have pushed for the re-scheduling of the drug - politics played a factor in legalization (tax income) - “BREAKING NEWS” - federal initiative to re-schedule (to Schedule 3) has been started: as of May 16, 2024 38  Take Home Points The use of “drugs” for medicinal, ritual, and recreational uses extends back in history to the earliest dates of humankind - most were plant based - has been part of our “diet” since the beginning of complex organisms There was evidence of principles, know-how, and scientific exploration for the appropriate use of chemical substances Some of the drugs discovered in ancient times are still in use today - tendency over time to isolate active ingredients for more potency (good and bad) - accepted use of particular substances depended on societal mores of a given culture or period/time 39  To do for Next Class (2 weeks from now) Read text chapters 2 (LO 2.3 2.10-2.16), and 4 (LO 4.10-4.14) Glia cells Neural Communication Ion Channels Neurotransmitters Part A and Part B Modern Drug Development 40 41 Final thoughts… 42