NROSCI 0081 Block 2 Exam Notes
NROSCI 0081 Block 2 Exam Notes NROSCI 0081
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This 33 page Study Guide was uploaded by Nicole Riggs on Monday February 29, 2016. The Study Guide belongs to NROSCI 0081 at University of Pittsburgh taught by Fanselow,Erika in Fall 2015. Since its upload, it has received 135 views. For similar materials see DRUGS AND BEHAVIOR in Neuroscience at University of Pittsburgh.
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Date Created: 02/29/16
Block 2 Neuronal Communication (1) What are neurons for, anyway? Most neurons are highly specialized to: o (1) Receive signals from the environment or from other neurons o (2) Make a “decision” based on those signals o (3) If that decision is “yes”: send their own signal All of these processes must be accurate & fast. So how do neurons do it? The need for speed Most cells have something called a “membrane potential” We’ve already talked about what a cell membrane is… & “potential” is a word that can be used to refer to “voltage”… But, what do “membrane” & “voltage” have to do with one another? What is voltage? A formal definition of voltage: the electrical potential at any point is defined as the energy required to bring a unit test charge from an infinite distance slowly to that point. It is usually measured in volts, & one volt is the potential for which one joule of work must be expended to bring a charge of one coulomb from infinity. This is accurate, but a bit too involved for our purposes here Put quite simply, a voltage occurs when there are more charges (say, negativelycharged molecules or ions) in one place (say, inside a neuron) than in another place (say, outside a neuron) Voltage + cell membrane = membrane potential For a neuron, there are more negative ions inside than outside This difference in charged ions creates a voltage (a.k.a. “potential”) Because the cell membrane separates these charges, the whole phenomenon is called a “membrane potential” How do we know a neuron has a membrane potential? Electrodes can detect the relative amounts of charges from ions inside & outside neurons What does an electrode measure in a neuron? The membrane potential tells you how many more negative ions are inside the neuron vs. outside CONCEPT #1: Neurons use membrane voltage to send signals along axons & cause neurotransmitter to be released Things to remember about how neurons use voltage to send a signal: o Ions move in & out of neurons through ion channels o There are three critical ions inside & outside of neurons. These are: (1) Sodium (Na+) Block 2 (2) Potassium (K+) (3) Chloride (Cl) o When ions move in & out of a neuron, this changes the membrane potential o If the membrane potential reaches a certain voltage, known as the “action potential threshold”, the neuron will send a signal, known as an “action potential”, to its axon to release neurotransmitter. Ions move through channels that open up in neurotransmitter receptors when a neurotransmitter binds Characteristics of ion channels: o When an ion channel is open, ions can flow through o Most ion channels are selective: they only allow one type of ion to go through o Ion channels can be opened, or “gated”, in multiple ways: (1) Ligandgated: opened by the binding of neurotransmitter or drug (2) Voltagegated: opened when the membrane voltage reaches a certain value Ions inside & outside neurons: Potassium (K+) The amount of K+ is higher on the inside of neurons When K+ channels open, K+ goes out of the neuron Ions inside & outside neurons: Sodium (Na+) The amount of Na+ is higher on the outside of neurons When Na+ channels open, Na+ goes into the neuron Ions inside & outside neurons: Chloride (Cl) The amount of Cl is higher on the outside of neurons When Cl channels open, Cl goes into the neuron CONCEPT #2: Ions are charged, so when they go in or out of a neuron, they change the value of the membrane potential If Na+ goes in, the membrane potential gets less negative If K+ goes out, the membrane potential gets more negative If Cl goes in, the membrane potential gets more negative Na+ flow can make the membrane potential depolarize above its resting (normal) level If Na+ channels open, the inflow of Na+ ions will push the membrane potential less negative, which is also referred to as being “depolarized” Depolarization is also said to “excite” a neuron K+ & Cl flow can both make the membrane potential hyperpolarize below from its resting (normal) level If K+ channels open, K+ flow will push the membrane potential more negative, or “hyperpolarized” If Cl channels open, Cl flow will push the membrane potential more negative (hyperpolarized) Block 2 Hyperpolarization is also said to “inhibit” a neuron If lots of Na+ channels open… If LOTS of Na+ goes in, the membrane potential depolarizes A LOT If Na+ goes in, the membrane potential depolarizes …& the membrane potential reaches the “action potential threshold”……suddenly, voltagegated Na+ channels open up……& open, & open, & open……until finally K+ channels open & get things back to normal. CONCEPT #3: Reaching the action potential threshold triggers a rapid, allornothing signal that can travel all the way to the end of an axon If the membrane potential reaches the action potential threshold, the entire action potential sequence will happen o Action potentials happen very quickly If the depolarization is not enough, no action potential will occur The membrane potential can wander up (depolarize) & down (hyperpolarize) How does an action potential resemble a toilet flush? Resting (normal) membrane potential = full tank of water With insufficient push of the handle, you get a transient flow of water, but no flush With sufficient push of the handle, get an allornothing flush Refractory period after the flush Action potentials start at the soma & travel to the axon terminal How fast do action potentials travel? Unmyelinated axons transmit an action potential at ~0.510 meters per second Myelinated axons transmit action potentials much faster: up to ~150 meters per second The importance of myelin: multiple sclerosis Characterized by a loss of myelin Autoimmune disease in which the body’s immune system attacks the CNS, leading to demyelination Prevents neurons from effectively conducting action potentials Can lead to many neurological symptoms; most commonly associated with sensory loss, fatigue, depression Block 2 Neuronal Communication (2) What does a synapse look like? How do neurotransmitters get from inside the neuron into the synaptic cleft? Synaptic vesicle fusion allows for neurotransmitter release Because the outer surface of a synaptic vesicle is made of the same type of molecules as the cell membrane, it can combine (fuse) with the cell membrane o (1) A vesicle containing neurotransmitter is near the cell membrane o (2) A group of molecules anchor the vesicle right on the cell membrane so it is ready fuse o (3) The arrival of an action potential triggers the vesicle to fuse rapidly with the membrane & thus release its neurotransmitter Neurotransmitter is released from synaptic vesicles into the synaptic cleft Since the synaptic cleft is narrow (1520 nm), the newlyreleased neurotransmitter molecules are close to the postsynaptic receptors & can bind to them But, if the neurotransmitters stayed in the synaptic cleft, there would be at least two problems: o The postsynaptic cell would respond indefinitely to the signal from the presynaptic neuron o There would be no way to send a second, separate, signal; the neurotransmitter released from one action potential would simply merge with that of the first How are neurotransmitters removed from the synaptic cleft? Block 2 3 methods by which neurotransmitters & drugs can be cleared from the synaptic cleft: o (1) Degradation (metabolic inactivation): neurotransmitter molecules or drugs can be broken apart by enzymes o (2) Reuptake: neurotransmitter can be brought back into the presynaptic neuron via proteins in the cell membrane known as transporters (Note that no neurotransmitter or drug molecules get taken into the postsynaptic neuron) o (3) Reuptake by glial cells: neurotransmitters can be moved into glial cells via transporter proteins in their cell membrane Two main categories of neurotransmitter receptors 1) Ionotropic & 2) Metabotropic (1) Ionotropic receptors let ions into or out of a neuron through a channel in their center o The channel is directly opened by the ligand, which changes the shape of the receptor o Terminology: When a receptor lets a specific ion through, it is said to be “permeable” to that ion (2) Metabotropic receptors bind ligands, but the binding of the ligand only affects the function of the neuron indirectly, through a series of other molecules inside the neuron How do neurotransmitters & drugs change how neurons behave? Many neurotransmitters & drug effects reduce down to this: What do the receptors they affect DO? o There are “families” of similar receptors that all can be affected by one type of neurotransmitter o Receptors within these families do not necessarily have the same effects on a neuron. Sometimes they can have opposite effects, even when binding the same neurotransmitter or drug o Drugs sometimes affect all the receptors in such a “family”, but often only affect a subset of them. Also, drugs may or may not do the same thing as the neurotransmitter that usually binds to the receptor. Pulling neuronal activity in two opposing directions Two main effects of receptors on the post synaptic cell that we will consider: o (1) Excitation of a neuron: makes the membrane potential of the postsynaptic cell more depolarized (less negative). This increases the likelihood that the postsynaptic neuron will initiate an action potential & release neurotransmitter o (2) Inhibition of a neuron: makes the membrane potential of the postsynaptic cell more hyperpolarized (more negative). This decreases the likelihood that the postsynaptic neuron will initiate an action potential & release neurotransmitter. How does one know whether a given receptor will cause excitation or inhibition? Block 2 EPSPs & IPSPs If Na+ channels open, Na+ flow will push the membrane potential less negative (depolarized) If K+ channels open, K+ flow will push the membrane potential more negative (hyperpolarized) If Cl channels open, Cl flow will push the membrane potential more negative (hyperpolarized) ESPs vs. IPSPs: which type of dendritic input “wins”? Excitatory neurotransmitters bind to receptors opening ligandgated Na+ channels producing EPSPs in postsynaptic neuron Axon hillock reaches threshold of activation triggering an action potential Inhibitory neurotransmitters bind to receptors opening ligandgated K+ or Cl channels producing IPSPs in postsynaptic neuron IPSPs counteract EPSPs; threshold of activation is not reached so no action potential is generated Neurotransmitters For each neurotransmitter, we will consider: Receptors, removal from the synaptic cleft, & behaviors or functions it is associated with (1) Amino acid neurotransmitters: amino acids are small molecules that are the building blocks of proteins, and two neurotransmitters are closely related to these molecules o Glutamate o GABA (2) Monoamines: o Dopamine o Norepinephrine o Serotonin (3) Acetylcholine Amino acid neurotransmitters: glutamate Glutamate is the primary excitatory neurotransmitter (causes EPSPs) in the CNS (brain & spinal cord) Ionotropic glutamate receptors affect neurons in two ways: o Indirect effects inside the neuron due to calcium (Ca2+) Metabotropic glutamate receptors affect neurons by initiating sequences of intracellular chemical reactions: o Changes neuron function via chemical reactions inside the neuron Glutamate removal from synaptic cleft Terminology: Transporters are proteins in neuronal or glial cell membranes that vacuum up neurotransmitters into these types of cells Glutamate is removed from the synaptic cleft in two ways: o Uptake into glial cells by glutamate transporters Block 2 o Reuptake in to the presynaptic neuron by glutamate transporters Functions of glutamate Glutamate is found widely in the brain & spinal cord (CNS) Glutamate plays a key role in learning & memory because it activates receptors that can change the strength of a synapse If there is too little glutamate, or if glutamate receptors are blocked, the brain can’t function normally Too much glutamate can cause seizures Amino acid neurotransmitters: GABA GABA is the primary inhibitory neurotransmitter (causes IPSPs) in the CNS (brain & spinal cord) There are two types of GABA receptors: o (1) GABAA receptor Ionotropic Cl permeable Have multiple binding sites for a range of ligands Inhibits neurons very quickly o (2) GABAB Metabotropic The subtype we will consider is K+ permeable Inhibits neurons more slowly GABA removal from synaptic cleft GABA is removed from the synaptic cleft in two ways: o Uptake into glial cells by GABA transporters o Reuptake in to the presynaptic neuron by GABA transporters Functions of GABA GABA is found widely in the brain & spinal cord (CNS) GABA receptors are affected by many drugs, including: o Alcohol, barbiturates, & benzodiazepines If there is insufficient GABA function, this can lead to seizures because there can be too much neuronal activity & the GABAergic neurons cannot control it well enough If there is too much GABA function (for example, if too many GABA receptors are activated), brain function becomes slower & disorganized, movements become uncoordinated, & breathing may be suppressed. The monoamines Monoamines get their name because each neurotransmitter molecule has one chemical part called an “amine” The monoamines include: o Dopamine, norepinephrine, & serotonin Dopamine receptors Block 2 Whereas dopamine can activate all dopamine receptors, there are drugs that will affect only one type or another There are five types of dopamine receptors, but they each have different effects on neurons All dopamine receptors are metabotropic This dopamine (DA) receptor indirectly blocks those same changes in neuron function. This dopamine (DA) receptor indirectly initiates various changes in neuron function. Block 2 Dopamine removal from synaptic cleft Dopamine is removed from the synaptic cleft in two ways: o Reuptake into the presynaptic neuron by dopamine transporters o Degradation by enzymes Functions of dopamine Dopamine neurons supply dopamine to the basal ganglia : o Involved in initiating voluntary movement o Lack of function cause Parkinson’s Disease Dopamine neurons also supply dopamine to the limbic system & frontal cortex o Involved in drug addiction & schizophrenia Norepinephrine locations & effects Norepinephrine affects: o Levels of attention/wakefulness o The autonomic nervous system o Cognition o Memory function Noradrenergic neurons project to many locations in the brain. Serotonin (5HT) receptors, locations, & effects 5HT receptors have many types & subtypes (15++?) that affect neurons in multiple ways Serotonergic neurons projects to many locations in the brain. Serotonin is removed from the synaptic cleft by reuptake into the presynaptic neuron via a serotonin transporter Acetylcholine receptors & removal from synaptic cleft There are two types of acetylcholine receptors: o (1) Nicotinic Ionotropic Excitatory Nicotine can bind to them o (2) Muscarinic Metabotropic Muscarine, a toxin found in some mushrooms, can bind to them After release into the synaptic cleft, ACh is broken down by the enzyme, acetylcholinesterase (AChE) Acetylcholine locations & effects Effects of acetylcholine: o Sleep/wakefulness o Sensory processing o The autonomic nervous system o Causes muscles to move Many toxins act as acetylcholine receptors (for example: botulinum toxin [botox]) Cholinergic neurons can be found all over the brain. Block 2 Block 2 Addiction (2) Addiction: a hijacking of the brain Addiction has been attributed to many factors (“morals”, brain chemistry, mental illness, trauma, the “wrong” friends…) Drug use can have extremely negative effects on many aspects of life Why do the shortterm rewards win out? o Because drugs can hijack the brain’s “reward pathway” and allow/cause the brain to learn really, really, well that drugs = pleasure “This isn’t just true for certain people who lack willpower or who are engaged in a deviant lifestyle. It is true for everyone who has a brain. It automatically becomes easier to understand why addiction is such a common problem across cultures.” Certain behaviors are important for survival What if the brain could enhance the likelihood of repeating these behaviors, without necessarily needing the original signal to do them? Hunger or instinct Initiation or repetition of a behavior Behavior: eating & mating Survival The brain’s “reward pathway” causes us to enjoy activities or substances that are critical for survival Hunger or instinct Initiation or repetition of a behavior Behavior: eating & mating Reward (such as, sugar, sex) That was pleasurable Initiation or repetition of a behavior & so on & so on & so on What is the “reward pathway”? The main job of the brain’s reward pathway is to get us to recognize things that “feel good” and then do them again, without necessarily having the initial trigger or instinct (for example, hunger) This combines several brain functions: o (1) Identifying that the result of a behavior felt good (“rewarding”) o (2) Associating “that felt good!” with “how and where did I do/get that?” o (3) Doing the rewarding behavior again o (4) “Reinforcing”/learning the associations Reward pathway inactivation If the reward pathway is weakened, (e.g. the synapses between neurons in this pathway become weaker or there is less neurotransmitter), the rewarding behaviors can still be done, but there is little motivation for doing them Reward pathway enhancement Block 2 In contrast, if neuronal activity in the reward pathway is enhanced, such as by stronger synapses or more neurotransmitter available, there is a high level of motivation for repeating the rewarding behaviors Why is the reward pathway relevant in addiction? Many addictive drugs strongly reinforce this reward pathway “Addiction is so powerful because it mobilizes basic brain functions that are designed to guarantee the survival of the species” Desire to take a drug Initiation or repetition of drug seeking Behavior: taking a drug Reward (effect of drug, such as feeling high) That was REALLY pleasurable! Desire to take drug & initiation or repetition of drug seeking & so on & so on & so on What is the anatomical basis for the reward pathway? Main Brain Areas involved: o Ventral tegmental area (VTA): sends dopamine to the other areas listed here o Hippocampus (HC): memory o Amygdala (amyg.): fear, memory for emotional events, reward value o Nucleus accumbens (NAc): reward o Prefrontal cortex (PFC): planning, goals, memory What is the neurochemical basis for the reward pathway? The neurotransmitter (neuromodulator), dopamine, is critical for the reward pathway. If a reward occurs, dopamine levels will increase Natural rewards elevate dopamine levels Many drugs increase dopamine release in the reward pathway Amphetamine, cocaine, nicotine, morphine The brain can adapt to having increased dopamine in the reward system Repeated activation of the reward pathway can cause biochemical changes in the pathway itself In response to a constant barrage of dopamine, the neurons will try to reduce the amount of dopamine they receive so they can get back to a normal working range of activity o Dopamine receptors can be downregulated if the reward pathway is stimulated too much and/or too frequently What does a downregulation of dopamine receptors mean for the reward pathway? For example: alcoholics, meth addicts, & heroin addicts end up with low levels of one type of dopamine receptor, which turns down the association between reward & the pleasurable feeling previously experienced from the drug: o Desire to take drug Initiation or repetition of a behavior Behavior: take a drug Reward (effect of drug, such as feeling high) That was somewhat (downregulation of dopamine receptors weakens this message) pleasurable Desire to take drug Initiation or repetition of a behavior & so on & so on & so on Block 2 What are the effects of a downregulated reward pathway? Since there are fewer dopamine receptors, it is difficult to reach the same high. Thus, addicts will go on binges to “chase the high”, but this doesn’t work; the response to the drugs simply cannot be the same. This is a form of drug tolerance. The effects of tolerance: higher dose required A higher does of a drug is needed to get the same effect (such as, pain relief or a high) as the first use The effect of tolerance: reduced maximum effect The same dose of a drug causes a smaller effect than with the first use Types of tolerance: metabolic tolerance From lecture 3: the process of creating or destroying biological molecules is known as metabolism o Metabolism tolerance: this occurs when repeated use of a drug reduces the amount of drug that is available in the target tissue, such as the brain. How does this happen? o The liver breaks down drug molecules with enzymes so they can be excreted. o But, the enzymes that break down drugs are not very specific; each enzyme can break down many types of molecules o Humans have ~2030 enzymes that break down drugs o When the liver encounters frequent doses of a drug that is broken down by a given enzyme, it makes more of that enzyme o Thus, the drug gets broken down & eliminated from the bloodstream faster One consequence of metabolic tolerance: o People who smoke regularly make larger amounts of the enzymes that break down substances in the smoke (including nicotine). This means that any drugs that are broken down by those particular enzymes are broken down much faster. This means smokers respond differently & may need higher doses of therapeutic drugs that are broken down by the same enzymes that are upregulated in response to smoking. Types of tolerance: pharmacodynamics tolerance Pharmacodynamic tolerance: occurs when changes in neuron function compensate for continued presence of a drug. Why would neurons change function in the chronic or frequent presence of a drug? The brain tries to maintain homeostasis: if activity of neurons within areas of the brain is not maintained within a reasonable, balanced, working range, it will not function properly Block 2 There are processes in the brain that allow it to adapt in order to get back to a homeostatic (functional) state. Downregulation of neurotransmitters is one such process. What happens if the reward pathway is downregulated & the drug is then suddenly unavailable? The reward system has come to “expect” a specific drug, so when people stop taking it quickly, there is much less activation of the reward system, which removes the pleasure component A corollary of this is that some recovering cocaine addicts say they do not feel pleasure in anything for a while after they stop using cocaine Cocaine General characteristics of stimulants Stimulants include cocaine, amphetamines, caffeine, and nicotine (plus derivatives of these) Stimulants, in general, cause sense of energy, alertness, purposeful movement, but some also cause euphoria Another term for these is “psychomotor stimulants” Drug classes for cocaine & amphetamines are all in the DEA Schedule I (no accepted medical use & high probability of abuse), except drugs used for ADHD because they have medical use (Schedule II). History of cocaine Cocaine is in the leaves of several species of plants, including ones that grow commonly in the Andes mountains in South America Leaves from coca plants can be chewed to get a stimulating & appetite suppressant effect; this does not usually lead to addiction Coca was imported to Europe & chemists purified cocaine from it, which made it possible to take cocaine in much higher doses & more quickly, increasing the high, but also the possibility of addiction “I would rather have a life span of ten years with coca than one of 1,000,000 centuries without coca” –Italian neurologist, Paolo Mantegazza Popularity of cocaine increased in Europe & the US 1869: Vin Mariani was a “medicinal” wine made by steeping coca leaves in wine, and it became the rage of Europe Then, cocainecontaining tonic, including CocaCola, was sold in the US Commonly used forms of cocaine (1) Powder: o Purified directly from coca leaves Block 2 o Can be cut with other white powders, either innocuous ones such as cornstarch or talcum powder, or with caffeine, amphetamine, or fentanyl (an opioid analgesic; this frequently makes for a deadly combination) (2) Freebase cocaine: o If cocaine is treated with various chemicals, it can be isolated in a chemically “free” form that is more readily smoked (3) Crack: o Solid chunk of cocaine o Prepared by boiling the powdered form with sodium bicarbonate (baking soda) Pharmacokinetics of cocaine: Routes of absorption With any method, what matters is not the blood levels, but the amount that actually gets to the brain. Since cocaine is somewhat fatsoluble, it can pass readily through the bloodbrain barrier so it can reach high concentrations in the brain Ingestion (such as with chewing coca leaves) is not very effective, in part because the liver degrades the cocaine before it ever reaches the brain (first pass metabolism) Snorting powder: o Relatively slow way to get cocaine in to the bloodstream (relative to inhalation or IV) o Blood levels rise relatively slowly, peaking after ~3060 minutes Inhaling cocaine from heated crack: o The cocaine is delivered to the bloodstream nearly as quickly as if injected o Peak blood levels occur within several minutes & are much higher than similar dose of snorted powder o High only lasts ~30 minutes Pharmacokinetics of cocaine: Inactivation Cocaine has a short halflife: ~0.51.5 hours Cocaine is rapidly broken down by liver & blood enzymes User is usually ready for another dose in 40 minutes or less The rapid increase in blood levels (which causes the “rush”) is followed by a rapid fall in blood levels (the “crash”). This can lead to cocaine binging Pharmacokinetics of cocaine: Inactivation & elimination HOWEVER: while the halflife of the cocaine itself is short, the breakdown products (metabolites) can be present in the urine for days following the last dose Pharmacodynamics of cocaine: effects on the brain Cocaine mimics the effects of the sympathetic division of the autonomic nervous system o Initiates the flightorflight response o Increases blood pressure & heart rate Block 2 o Narrows blood vessels Cocaine binds to reuptake transporters in the axon terminals for the following monoamine neurotransmitters: o Serotonin o Norepinephrine o Dopamine (this may be responsible for most of the effects of cocaine) Cocaine can also block voltagegated Na+ channels, so it can be used as a local anesthetic in medicine & dentistry (e.g. Novocain & xylocaine) Cocaine blocks dopamine reuptake by blocking the dopamine transporters Behavioral effects of cocaine Stimulants, including cocaine, are known for their ability to increase attention, cause alertness & eliminate fatigue Even Freud, who experimented with cocaine on himself, commented that the most probable use of cocaine would be for these properties: o “The main use of coca will undoubtedly remain that which Indians have made of it for centuries: it is of value in all cases where the primary aim is to increase the physical capacity of the body for a given short period of time & to hold strength in reserve to meet further demands…Coca is a far more potent & far less harmful stimulant than alcohol, and its widespread utilization is hindered at present only by its high cost.” Via injection or smoking: “The Rush” o A feeling of intense physical pleasure, euphoria, great selfconfidence & wellbeing; often compared to an orgasm If snorted or taken orally: o The feeling is less intense, and is more a sense of wellbeing Increased movement: o Constant motion: talking, moving, exploring, fidgeting o At higher doses, this movement becomes more focused & repetitive Psychoticlike state (delusions, hallucination): o This happens at very high doses and/or after prolonged use o Resembles psychotic schizophrenia o Can occur at the end of a severalday binge when blood levels are very high Shortterm physiological & psychological effects of cocaine As blood levels rise to toxic levels: Initially, the effects are exaggerations of the typical response to cocaine: o Energy & alertness become jitteriness, paranoia, and hostility o Increased movement becomes repetitive aimless activities o Mild increase in heart rate becomes palpitations or chest pains Later effects include: o Headaches, nausea/vomiting, strokes, heart attacks, seizures Block 2 o In fact, seizures are so common that an adolescent or young adult arriving at an emergency room with a seizure without previous history is almost always screened for cocaine use Longterm physiological & psychological effects of cocaine Due to constriction of blood vessels, cocaine can cut off the blood supply to the area of administration (e.g. ulcers in lining of the nose for snorting, bleeding in the lungs for smoking) Suppression of appetite can cause malnourishment Damage to heart Panic attacks Neurological changes such as loss of brain tissue & function (for example, an inability to think & remember) Paranoid psychosis, including hallucinations such as “cocaine bugs”: hallucinating that there are tiny creatures crawling all over one’s skin Cocaine tolerance & binges Tolerance to cocaine can happen rapidly, sometimes in a single “run” of multiple doses: o More frequent or higher doses are required (“chasing the high”) o Rapidlydeveloped tolerance can also reverse rapidly Users can go on cocaine binges: o Bouts of repeated use from hours to days with no sleep o The only important thing is maintaining the high o All available supplies will be consumed 3 stages to end of a binge (abstinence syndrome): o (1) Crash: exhausted, depressed mood o (2) Withdrawal: inability to experience normal pleasures, lack of energy, anxiety, craving for more cocaine o (3) Extinction: withdrawal symptoms subside Cocaine withdrawal Cocaine withdrawal is rarely lethal Typical symptoms of cocaine withdrawal: o Exhaustion/excessive sleep o Depressive symptoms o Rebound in appetite o Inability to feel pleasure of any kind This inability to feel any pleasure is considered one of the major reasons people start using again In longtime users, craving for cocaine can last for months Social consequences of chronic cocaine use Increasing hostility, paranoia, and belligerence associated with higher blood levels of stimulants result in more overt violence Block 2 Many highdose stimulant users become increasingly convinced that people are “out to get them”, and they become more agitated & inclined toward action In a country with relatively unrestricted gun laws, this combination can be lethal & often is “Crack babies” Use of crack during pregnancy can harm the fetus: o Premature birth o Low birth weight o Strokes o Brain damage o Death Note that these are not unique to cocaine use; they can be observed with use tobacco as well. This may be because both cocaine & nicotine constrict blood vessels that supply blood to the fetus Longterm prospects for such children include higher rates of learning disabilities and ADHD Cocaine in combination with heroin Some users take cocaine & heroin together, and the effect is like adding the two: the “dreaminess” of opiates takes the edge off the “jitteriness” of the cocaine But, this combination can be particularly lethal because usually the jitteriness of the cocaine will often cause users to stop when it gets too intense Thus, without that “brake”, overdose of either drug is more likely This combination was being used by Chris Farley, John Belushi & Chris Kelly when they died What can lead to cocaine addiction? Cocaine is highly addictive: because cocaine affects dopamine levels, it can be viewed as simply substituting a drug for natural reinforcers such as food and sex But, not all people who use cocaine become addicted, so what are the potential differences? Those who typically do not become addicted: o Strong anxiety response as their initial response to cocaine o Unavailability/cost o Social & legal consequences o Fear of becoming addicted Those who typically do become addicted: o Friends & acquaintances respond well to the user’s newfound energy & enthusiasm o Psychiatric disorders (e.g. depression, anxiety) o Exposure to location where or people with whom cocaine was previously used Block 2 Treating cocaine addiction: Behavioral/psychosocial strategies (1) Counseling (individual or group) o Educate user o Promote behavioral change (for example, avoid situations that put user at high risk for relapse) (2) 12step programs such as Narcotics Anonymous (3) Contingency management program: o Behavioral treatment based on the idea that drug taking is in part a result of the reinforcing property of a drug o Develop reinforcers that are not drugrelated o For example, if a person has a negative urine test (no cocaine or cocaine metabolites present), he or she will get a voucher for items (not money, as it could be used to buy drugs directly) o This may be more effective than standard behavioral therapies Treating cocaine addiction: pharmacological strategies (1) Reduce euphoric effects of cocaine and/or craving upon cocaine withdrawal: o Receptor agonists & antagonists that might compete with cocaine for access to the dopamine transporter o Antabuse: usually used for treatment of alcohol dependence. Many cocaine users abuse alcohol, and Antabuse seems to help with both drugs, AND can be effective for users of only cocaine (2) “Cocaine vaccines” o Attach molecules called antibodies to the cocaine molecules o This prevents cocaine from binding to the dopamine transporters o Mixed results so far, but this is an active area of research Amphetaminelike Drugs All of the following are stimulants, but subtle differences in the structure of the drug molecules cause them to have different effects on the brain o Amphetamine o Methamphetamine (“meth”) o Adderall (combination of four versions of amphetamine) o Ritalin (methylphenidate) o Diet pills o “Bath salts” These are not naturallyoccurring substances Development of amphetamine & meth Block 2 The Chinese drug, mahuang, had been known to treat symptoms of asthma for thousands of years The active compound was determined to be ephedrine: o Became a treatment for asthma o In 1990s, was considered an “herbal” treatment for asthma & other diseases, but had toxic effects & thus was regulated (sound like a familiar pattern?) But it is difficult to get much ephedrine from this plant o In an attempt to develop a synthetic ephedrine, amphetamine was developed o Independently, methamphetamine was developed by a chemist in Japan Early uses for amphetamine In the 1930’s, amphetamine was prescribed for depression Amphetamine was distributed to military personnel in WWII, and especially used by pilots to remain awake on longrange bombing missions Diet pills Stimulantbased diet pills were originally amphetamine o This started around WWII with the use of amphetamine for weight loss o The appetitesuppressant effects probably result from the release of norepinephrine & serotonin o Impossible to separate the appetitesuppressant effects from the addictive potential, which arises because of the release of dopamine A newer medication, Meridia, acts more selectively on norepinephrine & serotonin o Lacks abuse potential of amphetamine o But the effects on norepinephrine caused cardiovascular problems, so it was withdrawn from the market Pharmacokinetics of amphetamine & meth The molecules are very similar but the small difference does influence how they affect the monoamine systems Unlike cocaine, they can also be taken as pills because they are broken down more slowly by the liver One metabolite of meth is amphetamine These drugs have different halflives: Both much longer than cocaine, so a high lasts longer Amphetamine: halflife of 730 hours, depending on the acidity of the urine Meth: halflife of 10 hours Elaboration on the roles of monoamines in the nervous system The monoamines include: o Dopamine is involved in movement & the brain’s reward pathway, which is involved in reinforcing pleasurable things, including drug use Block 2 o Norepinephrine is involved in levels of attention/wakefulness & in memory formation o Serotonin affects eating behavior, anxiety, pain, learning Stimulants affect these systems, but because of subtle differences in the shapes of the molecules, different drugs affect them to different degrees & thus have different behavioral effects (such as the high, if there is one) Mechanisms of action for amphetaminelike drugs Amphetaminelike drugs do two things that increase monoamine levels in the synaptic cleft: o (1) Block monoamine reuptake (just like cocaine) o (2) Make the monoamine transporters work backwards, so they pump monoamine molecules out of the neuron Amphetamine & meth: behavioral effects Like cocaine, these drugs can cause heightened alertness, increased self confidence, exhilaration, sense of wellbeing Also: improved performance on simple, repetitive motor tasks, delay in sleep onset, reduction in sleep time Amphetamine can enhance athletic performance, so it is one of the primary substances banned in athletic competitions With heavy use, these can lead to psychotic reactions Therapeutic uses of amphetaminelike drugs Amphetamine o Prescribed for narcolepsy Ritalin (methylphenidate) o Prescribed for ADHD o Not amphetamine o Affects the dopaminergic system differently than the other monoamines (blocks dopamine reuptake, but does not cause dopamine release), so has less potential for addiction Adderall o Prescribed for ADHD o Combination of four slightly different versions of amphetamine Desoxyn o Prescribed for weight loss & ADHD o Is methamphetamine Other amphetaminelike drugs Khat: o From a plant native to East Africa & the Arabian peninsula o Contains an amphetaminelike stimulant, cathinone “Bath salts” o Contain synthetic cathinones o Usually much stronger than cathinone Block 2 o Halflives many times longer than cocaine or amphetamine o Overdoses & deaths are common Methamphetamine Street names: Crank, Chalk, Crystal, Fire, Glass, Go Fast, Ice, Meth, Speed Common forms: o White powder o Pills o Pure form that can be smoked: “crystal meth”, or “ice”; looks like pieces of glass or shiny bluewhite “rocks” of different sizes Common methods of administration: swallowed, snorted, smoked, injected Meth manufacture Meth is often made in small amounts in “smallcapacity production laboratories” (SCPLs) aka “onepot” or “shakeandbake” laboratories Meth can be made in small batches from relatively common ingredients The method for producing meth is dangerous because it creates a lot of heat & uses flammable materials, so there is the danger of explosions. This is a problem in part because SCPLs are often in residential areas Effects of meth on health: behavioral Anxiety, confusion, insomnia, mood disturbances, paranoia, psychosislike symptoms (delusions, hallucinations), which can last for months to years after someone stops using, methrelated psychotic symptoms can be triggered spontaneously by stress even after meth use has stopped Withdrawal symptoms include: depression, anxiety, fatigue, cravings Effects of meth on health: neurotoxic damage Chronic meth use can cause longterm neurotoxic damage : o Dopamine neurons do not die, but the axon terminals are “pruned” (cut back) so they are not available to release dopamine o These changes are associated with problems with memory & decision making o It is not yet clear whether these changes are reversible though there are some indications that they are with longterm abstinence Effects of meth on health: neurotoxic damage as evidenced by brain scans Effects of meth on health: physical Weight loss, tooth decay/loss of teeth (“meth mouth”), due to dry mouth & poor dental hygiene, skin sores, premature aging Alberto Gonzales, Attorney General under G.W. Bush said of meth that it was “the most dangerous drug in America” “This is the most malignant, addictive drug known to mankind” –Dr. Michael Abrams, New York Times, 1996 To stop the “meth epidemic”, limit sale of the precursor molecule(s) Is too much negative/exaggerated press a bad thing? Potential problems with exaggerating the hazards of meth Block 2 o (1) Encourages an overreaction that leads to overly harsh criminal penalties for meth use & possession (e.g. disproportionate/mandatory minimum sentencing guidelines) o (2) Fosters distrust of accurate warnings about drugs (“crying wolf”) o (3) Channels efforts & money into minimallyeffective policies (such as restrictions on the meth precursor pseudoephedrine) Caffeine What is caffeine? A mild psychostimulant Very widely used across the world ~8090% of adults in the US regularly drink caffeinated beverages, and ingest from 200400 mg of caffeine a day (~3 cups of coffee) Caffeine is produced by plants, but there are many (dozens? hundreds?) of other compounds in these plants that are also psychoactive & end up in tea, coffee, etc. History of caffeine use Tea: origins traced back to China in 4 century Coffee: o Discovered by goat herder because of effects observed in the goats (?) o First cultivated in Yemen in 6 century o By 1600’s, coffee had been introduced to Europe o Establishment of coffee houses o In 1760’s tea was heavily taxed in the English colonies, so coffee became the drink of choice Chocolate: o Used by early Central Americans in ~1100 B.C.E., primarily as a drink o Became popular to eat in 1800s when milk chocolate was invented in the Netherlands Caffeinated sodas: use rose greatly in the 1990’s Energy drinks: use skyrocketed in 2000’s Natural sources of caffeine Coffee: Made from “beans” of coffee bushes or trees, cultivated largely in equatorial regions Tea: Made from the leaves & buds of a plant that is native to China, Southeast Asia Chocolate: From the seed of cacao tree, mainly in West Africa Block 2 Pharmacokinetics of caffeine Typically consumed orally through beverages or pills Absorbed into bloodstream from digestive system (stomach & small intestine) in 3060 min; rate depends on amount of food in stomach & the concentration of caffeine ingested Halflife differs by person, but is usually ~34 hours Broken down mainly in the liver; smokers metabolize caffeine faster Mainly excreted in urine Behavioral effects of caffeine Generally known for its stimulating & fatiguereducing effects At low to moderate doses: o Alertness, energy o Enhancement of cognitive function, increased ability to concentrate At higher doses: o Tension & anxiety o Can trigger panic attacks in susceptible people At really high doses: o Can get caffeine poisoning, which can lead to irregular or rapid heartbeat, confusion, and seizures How does caffeine affect the brain? GABAA receptors Caffeine affects the brain & body in a number of ways, not all of which are understood Caffeine does NOT influence monoamine systems nearly as strongly as amphetaminelike drugs & cocaine do One way caffeine affects the brain: blocks GABAA receptors (inhibitory receptors) How does caffeine affect the brain? Adenosine receptors Caffeine’s main action on the brain is to block receptors for the neurotransmitter adenosine Since caffeine is an antagonist for adenosine receptors, it prevents adenosine from doing its job, which is thought to be the main reason for its stimulant effects This is neuronal activation via inhibition of an inhibitory effect: o No adenosine, no caffeine o With adenosine, neuronal activity and neurotransmitter release decrease o Caffeine blocks the adenosine receptors so the neuron can be more active & release more neurotransmitter Effects of caffeine on other parts of the body Heart: o Directly affects the heart: can increase heart rate & blood pressure, and can lead to irregular heartbeat Kidneys have adenosine receptors o Caffeine can promote urine production (is a diuretic) Block 2 Respiratory system: o Increases rate of breathing o Dilated air passages in the lungs Pharmacodynamic tolerance Some tolerance does develop: this is the brain’s attempt to maintain homeostasis Due to upregulation of adenosine receptors as the brain tries to deal with continued suppression of adenosine activity Tolerance to arousal and cardiovascular effects is observed Withdrawal symptoms are generally not sever (typically, headaches, fatigue, impaired concentration) Note that while caffeine intake can cause a physical dependence, it does not meet the overall criteria necessary to be considered an addictive drug Caffeine health risks *Possible* link with development of heart disease Can increase blood pressure at high doses or in susceptible people May increase cholesterol (but this is controversial) Digestive system: o Has been blamed for ulcers, but this link did not hold up (it can exacerbate them, though) Reproductive system: o Safe during pregnancy? Might cause low birth weight o May reduce chances of getting pregnant o Most studies do NOT support risk for breast cancer Health advantages of caffeine Can be used to treat migraine headaches: o Caffeine constricts blood vessels in the head and neck (adenosine relaxes them) o BUT: too much caffeine can trigger migraines, so there is a paradox here that has yet to be explained… Lower risk for heart arrhythmias (20%) and strokes in women (20%) Reduction in Parkinson’s disease risk (80%) Reduction in rates of some cancers Moderation may be key Caffeine combined with other drugs: Red Bull and Vodka Can caffeine counteract the effects of alcohol? In other words, can you reverse the effect of a sedative with a stimulant? Although caffeine does reduce alcoholinduced drowsiness, effects on manual dexterity, balance, reasoning, and verbal fluency remain (the phenomenon of “wideawake drunk”) A drunk driver may feel more alert after a few cups of coffee, but will still have impaired motor skills, reaction time, and decision making Block 2 Nicotine The tobacco plant and nicotine Grown in over 100 countries Grown on ~125,000 American farms Remains the most profitable crop per acre Different curing methods affect taste and nicotine content Nicotine is the main psychoactive ingredient in tobacco Nicotine is a psychostimulant, albeit a milder one than cocaine and amphetamine Crosses the bloodbrain barrier Nicotine: routes of administration Inhalation o Nicotine is vaporized by the heat at the end of a cigarette o It is inhaled attached to tiny particles called “tar” o Tar contains many things, some of which contribute to the taste and smell of cigarette smoke, and some of which are carcinogenic o Inhaled nicotine reaches the brain in 7 seconds, which is faster than if it were injected IV Across lining of the mouth or nose o Chewing tobacco (held in mouth), snuff (nose), “disk” (held under tongue) Transdermal patch (“nicotine patch”) o Nicotine goes through the skin into the bloodstream Nicotine metabolism Mostly
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