Fall 24 Exam 2 Review Slides PDF

Exam 2 Review Slides Neurotransmitters Small Molecule NTs: -Amino Acid NTs: Glutamate and GABA -Acetylcholine -Biogenic Amines: Serotonin, DA, Nor, and Ep Neuropeptides: -endogenous opioids Glutamate and GABA mediate fast neurotransmission Go! Glutamat...

Exam 2 Review Slides Neurotransmitters Small Molecule NTs: -Amino Acid NTs: Glutamate and GABA -Acetylcholine -Biogenic Amines: Serotonin, DA, Nor, and Ep Neuropeptides: -endogenous opioids Glutamate and GABA mediate fast neurotransmission Go! Glutamate Excitatory Neurotransmitter Depolarizes the postsynaptic membrane Slow down or Stop! GABA Inhibitory Neurotransmitter Hyperpolarizes the postsynaptic membrane  What determines if the amino acid neurotransmitter is excitatory or inhibitory? It all depends on receptor ALL neurotransmitters have multiple types of receptors, many have both metabotropic and ionotropic. In general, neurotransmitters can be said to be “excitatory or inhibitory”, because their receptors have those effects on the postsynaptic cell Other small molecule neurotransmitters Acetylcholine Acetylcholine First neurotransmitter discovered Excitatory neurotransmitter at: Neuromuscular junctions Autonomic nervous system synapses Important neuromodulator in the brain Receptors also bind Nicotine of ACh ACh is degraded in the synaptic cleft by acetylcholine esterase (AChE)  Venoms and ACh transmission Acetylcholine Esterase is a target… Many poisonous snakes have neurotoxic venom (especially the For drugs used to treat elapid snakes of Africa, Asia, and neuromuscular diseases and Australia). These venoms have Alzheimer’s Disease produced many valuable tools for For some animal venoms research. For insecticides and chemical weapons The venom of the green mamba contains a potent AChE antagonist. The venom of the Krait contains -bungarotoxin, which block ACh receptors irreversibly.  Small Molecule Neurotransmitters: Biogenic Amines Four main biogenic amine neurotransmitters called monoamines (contain 1 amine) Important in Psychopharmacology Norepinephrine Dopamine Serotonin indoleamine catecholamines Epinephrine Catecholamines- are removed by reuptake and by enzymatic degredation Degradation/removal of catecholamines Reuptake by Active Transporter (DA or NE) Monamine Oxidase (MAO enzyme) MAO inhibitors treat Depression, Parkinson’s  Serotonin Serotonin Synaptic Cleft Abbreviation: 5-HT Important roles: Prozac Sleep / Wakefulness Depression / Anxiety Serotonin X Transporter (SERT) Pharmacological interventions: Reuptake: Serotonin transporter Degradation: MAO Prozac: prevents serotonin reuptake and prolongs Serotonin neural responses to serotonin release Presynaptic Cell Diffuse Modulatory systems Biogenic Amines neurotransmitters and ACh Neurons project to many parts of brain Modulate overall brain states like mood, and arousal / sleep These systems are common drug targets https://www.slideserve.com/denton-vega/micro-neuroscience Diffuse Modulatory systems  Substance P VIP Neuropeptides Many neuropeptides are also hormones Roles in modulating emotion, pain, stress, homeostasis Co-localized Somatostatin with small molecule neurotransmitters CCK  Neuropeptides-Opioids Endorphin Named because they bind the same receptors that are activated by Opium Endogenous Opioid Peptides: 1. Endorphins 2. Enkephalins 3. Dynorphins Co-localized with GABA, serotonin Tend to be Depressants Act as analgesics, control Pain Addictive, Agent of Abuse Morphine, methadone, fentanyl  Pharmacodynamics Pharmacodynamics: study of the physiological and biochemical interaction of drug molecules with cell receptors in target tissue. Receptors: proteins on cell surfaces or within cells. Ligand: molecule that binds to a receptor with some selectivity. Most drugs do not pass into neurons, but act on surface receptors.  Pharmacodynamics: Agonists and Antagonists Most psychoactive drugs exert their effects by influencing chemical reactions at synapses Agonist Substance that INCREASES the effectiveness of a neurotransmitter For example, increases the postsynaptic response, EPSP or IPSP Antagonist Substance that DECREASES the effectiveness of a neurotransmitter For example, decreases the postsynaptic response, EPSP or IPSP or complete block = no or complete block = no response response Postsynaptic receptors Copyright © 2009 Allyn & Bacon  Pharmacodynamics Drug Neurotransmitter release Action at Synapses Agonists: promote neurotransmitter release Antagonists: decrease or block neurotransmitter release Receptor Interaction Agonists stimulate receptors bind to the postsynaptic receptors and open transmitter-gated ion channels or increase ionic current in the presence of a neurotransmitter Antagonists block receptors bind to the postsynaptic receptors and prevent opening of transmitter-gated ion channels Degradation Agonists: inhibit degrading enzyme Reuptake Agonists: block reuptake 20 Example of Drug Action: An Acetylcholine Synapse Nicotine, the active drug in tobacco, acts as an agonist and stimulates cholinergic receptors. Botulin toxin is the poisonous agent found in tainted food and it inhibits the release of ACh and therefore is an antagonist. Physostigmine is a drug that inhibits acethylcholinesterase, the enzyme that breaks down acetylcholine. Physostigmine therefore acts as an agonist to increase the amount of ACh available in the synapse. 22 Pharmacology: The Science of Drug Action Drug action: molecular changes produced by a drug when it binds to a target site or receptor. Drug effects: physiological or behavioral reactions The site of drug action may be different from the site of the drug’s effects. Morphine Cocaine, atropine Pharmacology: The Science of Drug Action Drugs act at several target sites, and have multiple effects. Therapeutic effects: the drug–target interaction produces desired physical or behavioral changes. All other effects are side effects. Pharmacokinetic Factors Determining Drug Action Bioavailability: amount of drug in the blood that is free to bind at target sites Pharmacokinetic component of drug action: the dynamic factors that contribute to bioavailability.  Routes of Administration Drugs must get into the nervous system. The way that a drug enters and passes through the body to reach its target is called route of administration. Oral Injection Inhalation Topical application Transdermal To bypass the blood-brain barrier: injection in the cerebro-spinal fluid or directly in the brain 26  Routes of Administration The route of administration affects the dosage of a drug, i.e. the amount of drug needed to have a psychoactive effect. Amphetamine 1000 mg - orally 100 mg - injected or inhaled 10 mg - injected into the CSF - cerebrospinal fluid 1 mg - injected directly into the brain 27  AbsorptionFigure 1.3 The time course of drug blood level depends on route of Absorption: Movement administration of the drug from site of administration to the blood circulation.  Absorption Factors that influence absorption Drug solubility Local conditions at the site of absorption, particularly in the gastrointestinal tract Stomach contents Concentration of the drug Generally high concentrations are absorbed more rapidly than low concentrations; Circulation to the site of absorption Increased blood flow due to massage or local application of heat enhances absorption of a drug The area of the absorbing surface Drugs are absorbed very rapidly in regions with large surface areas such as the lungs and the intestines  Distribution Highest concentration of a drug will occur where blood flow is greatest. Because the brain receives about 20% of the blood that leaves the heart, lipid-soluble drugs are readily distributed to brain tissue. The blood–brain barrier limits movement of ionized molecules.  Distribution: Drug Depots Drug depots: binding at inactive sites where no biological effect is initiated. Plasma proteins (e.g., albumin), muscle, and fat. Drug molecules tied up in these depots cannot reach active sites or be metabolized by the liver, but binding is reversible. Depot binding affects magnitude and duration of drug action: it reduces concentration of drug at its sites of action and delays effects. Depot binding can result in drugs remaining in the body for extended periods. THC can be detected in urine for many days after a single dose. Competition for depots: aspirin and phenytoin  Inactivation and Elimination Half-life: amount of time required for removal of 50% of the drug (t½). Half-life determines interval between doses. A drug given once a day should have a half-life of about 8 hours. Longer half-life could lead to accumulation, which increases potential for side effects and toxicity.  Inactivation and Elimination Metabolism Metabolism is the processes of destructing drug molecules Drugs are broken down in the kidneys, liver, and intestines. Most biotransformation (drug metabolism) occurs in the liver.  Inactivation and Elimination Metabolism First pass metabolism of drugs that are Live absorbed from the digestive system occurs r in the liver and for some drugs (like alcohol) Stomach also in the stomach and intestines. Alternative routes of administration avoid the Intestine first-pass effect E.g., intravenous, intramuscular, inhalational aerosol, transdermal and Hepatic portal sublingual vein Some therapeutic drugs also take this path and must be administered by injection, or in high doses.  Inactivation and Elimination Excretion The processes of eliminating waste products Drugs are excreted in urine, feces, sweat, breast milk, and exhaled air Urine is the most important route for drug elimination. The kidneys filter materials from the blood, unless they are large or bound to plasma proteins. Drugs can be excreted changed and/or unchanged  Basic pharmacology Time course of plasma cocaine (pharmacokinetics) concentrations following different routes of administration Extremely rapid absorption occurs with IV injection and smoking; slower with snorting and oral use. Once absorbed, cocaine is rapidly broken down and excreted; the subjective high lasts about 30 minutes. Metabolites can be detected in the urine for several days Cocaine plus alcohol produce a unique metabolite called cocaethylene – has activity similar to cocaine  Drug misuse/abuse: the use, generally by self-administration, of a drug in a way that deviates from the social norms of a given culture.  Drugs and Experience Tolerance Drug tolerance: diminished response to a drug after repeated exposure. Increasing dosages must be administered to obtain the same magnitude of biological effect. Cross tolerance: tolerance to one drug can diminish effectiveness of a second drug. Types: metabolic, pharmacodynamic, behavioral 38  Drugs and Experience Tolerance Metabolic tolerance Increase in number of enzymes used to break down substance Increase in drug bioavailability  Drugs and Experience Tolerance Pharmacodynamic tolerance: changes in nerve cell function compensate for continued presence of the drug. Examples: receptor down-regulation and up- regulation. Behavioral tolerance People learn to cope with being intoxicated Withdrawal Sudden cessation of drug use Causes a variety of symptoms: Sweating Shaking Nausea/Vomiting Sleeplessness Anxiety Loss of Appetite  Drug Addiction the term used to describe an overall pattern of compulsive drug abuse characterized by consistent preoccupation with drug consumption and a tendency to relapse after withdrawal. The point at which abuse or dependence becomes addiction is hazy. Brain disease- chronic, relapsing, despite negative consequences The point at which misuse or dependence becomes addiction is hazy. Reward positive effect or feeling Subjective (may or may not mean pleasure) Reinforcer: substance, event, or activity that increases frequency/probability of response that precedes it objective Discovering the Reward Areas of the Brain https://www.youtube.com/watch?v=uofQPL uLV9A Self Brain Stimulation Hippocampus -median forebrain Frontal Cortex Amygdala bundle Arcuate n. - ventral tegmental area Also: Caudate prefrontal cortex nucleus Nucleus nucleus accumbens accumbens Pituitary Substantia Ventral nigra Medial forebrain bundle tegmental area Mesolimbic Dopamine system Natural Rewards Elevate Dopamine Levels FOOD SEX DA Concentration (% Baseline) 200 200 NAc shell % of Basal DA Output 150 150 Copulation Frequency 100 100 15 Empty 10 50 Box Feeding 5 0 0 0 60 120 180 Female Present Time (min) Sample 1 2 3 4 5 6 7 8 Mounts Number Intromissions Ejaculations Di Chiara et al., Neuroscience, 1999. Fiorino and Phillips, J. Neuroscience, 1997. Drug self-administration Syringe pump Intravenous or intracerebral cannula Nucleus accumbens Mesolimbic pathway Ventral tegmantal area Hippocampus Frontal Cortex Amygdala Nucleus accumbens Arcuate n. Ventral tegmantal area Caudate nucleus Nucleus accumbens Pituitary Substantia Ventral nigra tegmental area How do drugs affect our bodies? Limbic system and neurotransmitters Alter normal functioning of these systems Increase in synaptic activity (especially dopamine) Alterations of dopamine activity receptors involved: D2, D3, D4 Brain area involved: nucleus accumbens  Effects of Drugs on Dopamine Release 1100 Accumbens AMPHETAMINE Accumbens COCAINE 1000 400 % of Basal Release % of Basal Release 900 800 DA DA 300 DOPAC 700 DOPAC HVA 600 HVA 500 200 400 300 200 100 100 0 0 1 2 3 4 5 hr 0 0 1 2 3 4 5 hr Time After Amphetamine Time After Cocaine 250 NICOTINE 250 Accumbens MORPHINE % of Basal Release % of Basal Release Dose (mg/kg) 200 Accumbens 0.5 200 Caudate 1.0 150 2.5 150 10 100 100 0 0 1 2 3 hr 0 0 1 2 3 4 5hr Time After Nicotine Time After Morphine Di Chiara and Imperato, PNAS, 1988  Neuroanatomy of drugs of abuse Frontal Cortex Amphetamine Cingulate Cortex Barbiturates Caffeine Cocaine Hypothalamus Septum Ethanol Lateral Habenula Morphine Ventral Nicotine Pallidum PCP DA Ventral N.Accumbens Tegmental Area Entorhinal Cortex Temporal Cortex Amygdala Anterior Cingulate Cortex Hippocampus Current View: Overt physical symptoms and psychological cravings are all manifestations of NEUROADAPTATION. Abnormal usurpation of pathways that under normal conditions mediate reward/learning/memory/motivation Circuits Involved In Drug Abuse and Addiction Dopamine D2 Receptors are Lower in Addiction DADA Cocaine DA DA DA DA DA DA DADA DA DA Meth Reward Circuits Non-Drug Abuser DADA Alcohol DA DA DA DA Heroin Reward Circuits Control Addicted Drug Abuser As a result, addicted subjects don’t feel “normal” unless they have dopamine levels increased by their drug of choice Epigenetic Processes and Synaptic Plasticity as Mechanisms for the Development and Persistence of Drug Addiction Incubation of craving for cocaine in a rat model Behavioral responses to cocaine associated cues increase as the This is associated with changes in glutamate signaling number of days since in the NAc the last cocaine exposure increases (cocaine withdrawal day)  Behavioral effects of cocaine Via injection or smoking: “The Rush” A feeling of intense physical pleasure, euphoria, great self-confidence and well-being If snorted or taken orally: The feeling is less intense, and is more a sense of well-being Increased movement: Constant motion: talking, moving, exploring, fidgeting At higher doses, this movement becomes more focused and repetitive Psychotic-like state (delusions, hallucinations): This happens at very high doses and/or after prolonged use Resembles psychotic schizophrenia Can occur at the end of a several-day binge when blood levels are very high 61 Mechanisms of cocaine action Cocaine increases synaptic DA levels by: -binding to the plasma membrane DA transporter and blocking reuptake of the neurotransmitter. This also occurs at serotonergic and noradrenergic synapses Time course of striatal cocaine and DA concentrations following rapid IV cocaine infusion Inhibition of DA reuptake can occur very rapidly, as shown by microdialysis studies  Cocaine: Mechanisms of action Cocaine also increases frequency of DA release it inhibits NE uptake in the PFC, causing an NE receptor– mediated stimulation of glutamatergic neurons that project to the VTA. At higher concentrations, cocaine also blocks voltage- gated Na+ channels leads to a local anesthetic effect. Amphetamines: Basic pharmacology Amphetamine: typically taken orally or IV or subcutaneous injection (skin popping) Absorption from GI tract is slow IV injection provides a rapid and intense “high;” has much greater addictive potential Methamphetamine: more potent; can be taken orally, snorted, injected intravenously, or smoked Methamphetamine hydrochloride in a crystalline form suitable for smoking is called “ice” or “crystal;” highly addictive Amphetamines: Basic pharmacology Some users go on binges or runs – repeated injections every 2 hours for 3 to 6 days, with little sleep or eating Amphetamine and methamphetamine are metabolized slowly by the liver metabolites are excreted in the urine Because of long half-lives, users obtain a much longer-lasting high from a single dose of amphetamine or methamphetamine than from a dose of cocaine. Behavioral effects of amphetamines heightened alertness increased confidence feelings of exhilaration reduced fatigue generalized sense of well-being Reduced sleep time, especially REM sleep; permits sustained physical effort without rest or sleep Can enhance athletic performance; banned in competitions At extremely high doses can also cause psychosis Mechanisms of amphetamine and methamphetamine action Stimulate massive DA release in two ways: Amphetamines are indirect catecholamine agonists stimulate DA and NE release and block reuptake NE release also affects sympathetic nervous Enters nerve terminal by Alters DAT to act in system DAT; stimulates DA release reverse direction to from vesicles release DA into synapse Summary of altered striatal dopaminergic markers in chronic psychostimulant users compared to non- using controls psychostimulant users showed 1.decreased DA synthesis (illustrated by fewer DA molecules per synaptic vesicle and fewer vesicles), 2.decreased DA release (illustrated by fewer DA molecules in the synaptic cleft), 3.less DAT binding 4.less DA receptor binding.  Psychostimulants and ADHD ADHD is characterized by extreme inattentiveness, impulsivity, and hyperkinesis thought to be related to dysfunction in complex neural circuits that include the PFC Psychostimulants have a seemingly paradoxical calming effect Methylphenidate (Ritalin) Activates catecholamine transmission by blocking DAT and NET - increases extracellular levels of DA and NE Doesn’t increase DA release- so less potential for abuse Nicotine: routes of administration Inhalation Nicotine is vaporized by the heat at the end of a cigarette It is inhaled attached to tiny particles called “tar” Tar contains many things, some of which contribute to the taste and smell of cigarette smoke, and some of which are carcinogenic Inhaled nicotine reaches the brain in 7 seconds, which is faster than if it were injected IV Across lining of the mouth or nose Chewing tobacco (held in mouth), snuff (nose), “disk” (held under tongue) Transdermal patch (“nicotine patch”) Nicotine goes through the skin into the bloodstream 71 Nicotine metabolism Mostly metabolized in the liver and then excreted via the kidneys The body can metabolize most of the nicotine from 1 cigarette in about 1-2 hours The rate of metabolism varies from person to person and is linked to abuse potential Nicotine and tar induce the production of liver enzymes which results in increased metabolism of other drugs 72 How does nicotine affect the brain and body? Nicotine is an agonist for nicotinic acetylcholine receptors (nAChRs) Ligand-gated ion channels that respond to the neurotransmitter acetylcholine Receptors let Na+, K+ and Ca2+ through, and the net effect is to depolarize neurons Nicotinic receptors are also used to signal muscles to contract 73 Nicotine stimulates the reward pathway Receptors for nicotine (α4β2 ) in NAc VTA cause VTA neurons to release more dopamine in the nucleus accumbens Nicotine binds to α7 nicotinic presynaptic receptors on glutamate (Glu) neurons in the VTA, stimulating glutamate release that in turn leads to dopamine release in the nucleus accumbens. Nicotine desensitizes α4β2 receptors on VTA GABA interneurons- disinhibits VTA DA neurons and leads to dopamine release in the nucleus accumbens 74  Behavioral and Physiological Effects of Nicotine Chronic exposure to nicotine induces tolerance and dependence Acute tolerance: brief; due to desensitization of central nAChRs Smokers undergo acute tolerance during the course of a day; after overnight abstinence, smokers awaken more sensitive to nicotine than at the end of the previous day. Chronic tolerance from long-term exposure: Smokers show an up-regulation of nAChR levels in many brain areas, may be a response to chronic receptor desensitization associated with repeated nicotine exposure 76 Behavioral and Physiological Effects of Nicotine Nicotine exerts both reinforcing and aversive effects Reinforcement can be influenced by many factors, including sex and age; females and adolescents are more sensitive The mesolimbic DA pathway from the VTA to the NAcc plays a key role Research using knockout mice: high-affinity nAChRs subunits β2, α4, and α6 are involved in reinforcement; polymorphisms in human genes for these subunits are linked to subjective effects of smoking and risk of dependence. Brain imaging shows nicotine occupancy of high-affinity α4β2 subunit–containing nAChRs  Behavioral and Physiological Effects of Nicotine Nicotine exerts both reinforcing and aversive effects Aversive effects: nausea, dizziness, sweating, headache, palpitations, stomach ache, and clammy hands Aversion is dependent on nAChRs containing the α5 subunit Knocking out the α5 subunit enhances nicotine self- administration at high doses Gene for the nAChR α5, subunit is on human chromosome 15; a mutation in the α5 gene results in less aversion to nicotine and heavier smoking behavior Nicotine withdrawal and addiction Nicotine causes physical dependence and addiction Symptoms of nicotine withdrawal: Anxiety Decrease in ability to enjoy anything Cravings Irritability Depressed mood Mild nicotine withdrawal can even happen overnight 79 Treatments for tobacco dependence 70-75% of smokers in the US would like to quit 40-45% try to quit each year Success rate for quitting is very low Treatment strategies: Prevention: health warnings on cigarette packs Self-help programs: these are often not of much benefit Individual or group therapy programs Pharmacological treatments: 1) Nicotine replacement (nicotine gum, patch, spray, inhaler, lozenges): goal is to reduce withdrawal symptoms 2) Non-nicotine drugs – most effective with behavioral intervention: Bupropion (Zyban), a DA and NE reuptake inhibitor and weak nAChR antagonist Varenicline (Chantix), a partial agonist at high-affinity α4β2 nAChRs. 3) Nicotine vaccine: no efficacy in clinical trials 80  Caffeine pharmacokinetics Methods of consumption Almost universally oral But transdermal works too Completely absorbed by GI tract in 30-60 minutes Average plasma half-life is 4 hours If you drink coffee throughout the day, your plasma levels keep going up Metabolism of caffeine is increased by nicotine and decreased by alcohol And also by pregnancy or birth control pills  Behavioral effects of caffeine Generally known for its stimulating and fatigue-reducing effects At low to moderate doses: Alertness, energy Enhancement of cognitive function, increased ability to concentrate At higher doses: Tension and anxiety Can trigger panic attacks in susceptible people 1 g (consumed quickly) is At really high doses: toxic, 5-8 g is lethal Can get caffeine poisoning, which can lead to That would be something irregular or rapid heartbeat, confusion and like 50 cups of coffee seizures 82 Behavioral effects of caffeine In lab animals, caffeine acts as a stimulant at low doses (increases locomotion) but decreases locomotion at high doses (why?) In people: increased arousal and decreased fatigue Positive subjective effects of enhanced vigor and increased concentration Could positive cognitive effects be due to relief from withdrawal symptoms? How would we test this?  How does caffeine affect the brain? Adenosine Adenosine builds up during wakefulness, Adenosine receptor locations creating a state of drowsiness It acts on four different receptor subtypes. 84  Adenosine accumulates in the brain during wakefulness… PET scan looking at adenosine A1 receptor distribution D. Elmenhorst  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 No adenosine, With adenosine, Caffeine blocks the main reason for its no caffeine neuronal activity and the adenosine neurotransmitter receptors so the stimulant effects release decrease neuron can be more active and This is neuronal activation via inhibition of an release more inhibitory effect neurotransmitter 86  How does caffeine affect the brain? Adenosine receptors Adenosine receptors form complexes with DA receptors in the striatum. Adenosine activation of striatal Adenosine receptors has a negative allosteric effect on DA receptors Blockade of adenosine receptors, particularly A2A subtype, underlies caffeine- induced behavioral stimulation 87  Caffeine pharmacodynamics At high doses, caffeine starts to have more “off-target” effects (all of which are excitatory) But almost all the effects experienced from a reasonable daily dose are from blockade of adenosine A1 and A2A receptors The A2A receptor type is especially prevalent in the striatum (nucleus accumbens!), where it inhibits D2 dopamine receptors Caffeine = (a little bit) more dopamine action Caffeine does NOT influence monoamine systems nearly as strongly as amphetamine-like drugs  Time course of caffeine withdrawal in regular users Chronic Caffeine Use Some tolerance does develop: this is the brain’s attempt to maintain homeostasis Due to up-regulation 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 severe (typically, headaches, fatigue, impaired concentration) 89  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 alcohol-induced drowsiness, effects on manual dexterity, balance, reasoning, and verbal fluency remain (the phenomenon of “wide-awake 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 90