Lectures 5 and 6: neuropharmacology
Lectures 5 and 6: neuropharmacology NSC 3361
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This 14 page Class Notes was uploaded by Rachael Couch on Thursday February 4, 2016. The Class Notes belongs to NSC 3361 at University of Texas at Dallas taught by Van S Miller in Summer 2015. Since its upload, it has received 71 views. For similar materials see Behavioral Neuroscience in Neuroscience at University of Texas at Dallas.
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Date Created: 02/04/16
Lectures 5 and 6: Neurotransmitters and neuropharmacology Ligands bind to two main classes of receptors Ionotropic – direct; ligand binds to ion channel which opens up a pore in the membrane o = Ligandgated ion channel Metabotropic –indirect; ligand binds to a receptor which causes some intermediate (usually a G protein) to dissociate from the receptor (inside the cytoplasm) and bind the ion channel causing it to open o Ion channel is near ligandbinding site but not next door o Often many intermediates, cascade of binding to open the channel Many places to target for drug therapeutics o More complex so more likely to go wrong o Used more often in the brain than ionotropic Agonist Anything that acts like the natural ligand Initiates normal effects of the receptor Antagonist Blocks the natural action of the ligand Competitive – compound competes with the natural ligand for the active site o When compound is bound no signal Noncompetitive – compound binds in site other than the active site o Either natural ligand can still bind partial signal o Or compound prevents ligand from binding in an indirect way o Most drugs are noncompetitive Both competitive and noncompetitive are temporary effects; reversible Neurotransmitters Chemicals that affect synaptic transmission by increasing or decreasing the chance of the neuron firing Classes of neuro transmitters Amino acids glutamate, aspartate, glycine, GABA (gagG) Monoamines o Catecholamines dopamine, epinephrine, norepinephrine o Indolamines serotonin Soluble gases nitric oxide and carbon monoxide Acetylcholine Neuropeptide endorphins Amino acids: Glutamate Most common excitatory neurotransmitter in the brain Glutamate binds to a receptor causing a sodium channel to open Ionotropic glutamate receptors o AMPA, NMDA, and kainite Metabotropic glutamate receptors o mGluRs (G proteincoupled receptors) Excitotoxicity – neural injury such as stroke or head trauma causes the excessive release of glutamate, which kills neurons Glycine The major inhibitory neurotransmitter in the spinal cord Strychnine blocks glycine and causes death o Symptoms appear within 20 minutes First neck stiffness, twitching muscles, and feeling of suffocation Later violent convulsions with body arched and head bent backward o After a minute muscles relax, but a touch or noise causes convulsions to recur, or they recur spontaneously, every few minutes o Do not lose consciousness = agonizing, fullyaware death o Rat poison has strychnine o Strychnine is a way to induce tetanus GABA Most common inhibitory neurotransmitter in the brain GABA iA an ionotropic gated Cl channel o Produces fast inhibitory effects GABA agonists, like valium and barbiturates, are potent tranquilizers o First drug of choice for a seizure is a GABA agonist o Very simple and likely to work because ionotropic GABA has a binding site for valium because the brain naturally makes its own valium Ethanol binds GABA o Too much alcohol binds to the GABA receptor and acts as a depressant Monoamines: Catecholamine synthesis Synthesized from tyrosine (from almost every food) Tyrosine hydroxylase (which converts tyrosine to an intermediate) is ratelimiting Intermediate dopamine –(enzyme) norepinephrine—(enzyme) epinephrine o If dopamine is never made then norepinephrine and epinephrine cannot be made Dopamine Made at the top of the brain stem then spreads throughout the brain Dopamine is involved in reward, addiction, reinforcement and learning, and schizophrenia Dopamine is projected into the basal ganglia and effects motor control o Involved in Parkinson’s disease Norepinephrine Made in the locus coeruleus (meaning blue spot) and spreads out in the brain o Starts in a line down the back of the brain stem Involved in mood, arousal, sexual behavior Serotonin Synthesized throughout the brain stem (scattered origins) and the spinal cord then spreads all over the brain Similar to norepinephrine Involved in sleep, mood, sexual behavior, anxiety, and depression Soluble gases/gas transmitters Nitric oxide (NO) is produced in dendrites and diffuses immediately Gases cannot be stored in the membrane because they diffuse through it o Can store dopamine, norepinephrine, etc. in a vesicle Serves as a retrograde transmitter by diffusing back into presynaptic neuron o Made in the postsynaptic neuron and diffuses to provide feedback to the presynaptic neuron Acetyl Choline Cholinergic pathways in the brain o Made in the basal forebrain = bottom of the brain (not the brain stem) Basal forebrain (thinking, memory, reasoning, intellect, emotion…) o Alzheimers begins in the basal forebrain acetyl choline is the first to be affected First function to be affected is thinking 2 kinds of receptors: nicotinic and muscarinic Nicotinic o Ionotropic o Excitatory o Peripheral in muscle (not brain) o Agonist Nicotine Binds and opens it allowing sodium to come inside the cell o Antagonist – Curare Curare paralysis but would not lose consciousness because receptors are not in the brain Muscarinic o Metabotropic o Can be excitatory or inhibitory o CNS – receptors in the brain o Agonist Muscarine o Antagonist – Atropine, scopolamine, Benadryl, cough/cold medicines that make you dizzy Alter cognition Neuropeptide Endogenous opiates – enkephalins, endorphins, dynorphins o Peptides that bind to opioid receptors and relieve pain (analgesics) o Addictive Endorphins are produced by the pituitary and hypothalamus during exercise (stressful/intense – marathon running, etc.), excitement (extreme excitement), pain, eating spicy food, love, and orgasm Endogenous opiates produce analgesia and a feeling of wellbeing o Any action that stimulates endogenous opiates can be addictive Neuromodulators Indirectly affect transmitter release or receptor response Adenosine o Normally released with catecholamines (dopamine and norepinephrine) o Inhibits catecholamine release via presynaptic autoreceptors o During wakefulness adenosine builds up, making us sleepy Caffeine o Blocks the effect of adenosine stimulates catecholamine release, causing arousal o Greater than 50% increased mortality risk in young people who drank more than 4 cups of coffee per day Sites of drug action Drugs can affect multiple sites like transport of molecules into the synapse, synthesis, storage of compounds… Ex: Low blood pressure drug causes “leaky” storage of adrenaline – which causes increase in blood pressure Drugs Antipsychotic (neuroleptic) drugs Class of drugs to treat schizophrenia, aggressive behavior, psychosis, and OCD Used in all ages, even young children that show excessive psychotic behavior Typical neuroleptics are dopamine (D )2antagonists Blocking the dopamine makes people calmer and more lucid o Accidentally discovered its use for schizophrenia when treated patient to prevent them from harming themselves/others Antidepressants Mostly act by causing the accumulation of monoamines 3 classes of antidepressants, only 2 used now o Each class became increasingly selective decreased side effects MAOIs Monoamine oxidase inhibitors prevent the breakdown of all monoamines at the synapse o Monoamine oxidase breaks down monoamines (serotonin, adrenaline, epinephrine) o An accumulation of adrenaline can be dangerous because inc. blood pressure o Not used anymore Tricyclics increase norepinephrine and serotonin at synapses by blocking their reuptake into presynaptic axon terminals SSRIs Selective serotonin reuptake inhibitors cause serotonin to accumulate in synapses, with fewer side effects than the tricyclics o Ex: Prozac, Zoloft o Too high of a dose = too much serotonin which causes mania Associated with an increased risk of suicide Anxiolytics/ tranquilizers Reduce nervous system activity Meditating/calming yourself acts on GABA receptors and causes a similar effect to anxiolytics Benzodiazepine o Benzodiazepine agonists act on GABA recAptors and enhance inhibitory effects of GABA via Cl influx o Causes hyperpolarization o Allopregnanolone endogenous benzodiazepine Barbiturates o First class of epilepsy drugs o Addictive o Noninhalation anesthetic used to put someone in a coma o Block sodium channels to prevent inflow of sodium ions o Barbiturates also increase flow of chloride ions across the neuronal membrane Together cause inhibition of neuron firing Alcohol Biphasic effect (stimulant then depressant) In low doses alcohol is a stimulant o Turns off cortical inhibition, reducing social constraints and anxiety o Causes relaxation then disinhibition o At low doses affects dopamine (DA) At higher doses alcohol has a sedative effect (depressant) o Impaired motor function, stupor, coma, then death (respiratory failure) o High doses affect GABA and NMDA Affects several neurotransmitter systems o Inhibits glutamate (excitatory) o Increasing binding of GABA at GABA receptor (inhibitory) A o Combined effect at glutamate and GABA receptors is sedation, anxiety reduction, muscle relaxation, inhibited cognitive and motor skills o Pleasurable effects come from stimulation of dopamine, opiate, serotonin, and cannabinoid receptors Seizures during alcohol withdrawal are due in part to a compensatory increase in the number of glutamate receptors over time Brain effects o Alcohol reduces brain metabolism o The brain is smaller in the alcoholic and the ventricles are larger o Alcohol damages neurons in the cerebellum and frontal lobe o Neurons can recover – brain looks closer to normal in recovering alcoholics Fetal alcohol syndrome o Alcohol has severe effects in the developing brain o Some women can drink a ton every day and have perfectly normal babies while some can drink moderately and have a child with fetal alcohol syndrome o Causes mild facial defects and microcephaly Opiates Can depress breathing by changing neurochemical activity in the brain stem o Brain stem controls automatic body functions Can change the limbic system (controls emotion) to increase feelings of pleasure Can block pain messages transmitted through the spinal cord from the body Morphine o Binds to opioid receptors in the brain stem, especially in the locus coeruleus and the periaqueductal gray o Opium contains morphine Heroin o Marketed by Bayer as a cure for codeine addiction before it was quickly discovered that heroin rapidly metabolizes into morphine Marijuana 5000 BC Indian medical practice used marijuana to treat appetite loss Active ligand is THC (tetrahydrocannabinoid) Effect o Wide range of effects o CB receptors are concentrated in brain areas that influence pleasure, memory, concentration, time perception, appetite, pain, and coordination o Negatively affects memory; impairs shortterm memory making it hard to learn complex tasks o Altered judgment and decision making o Slows reaction time – impairs driving skills o Altered mood euphoria, calmness; in high doses, anxiety, paranoia o Analgesic, decreases nausea, appetite stimulant Endocannabinoids – bind cannabinoid (CB) receptors o Anandamide and 2AG (2 arachidonoyl glycerol) o Retrograde signaling molecules released to activate cannabinoid receptors on nearby neurons o Act locally (only effect neurons in that site) because they are lipophilic (fat soluble) Can’t store in vesicles so they exist as part of the membrane o Synthesized “ondemand” Antagonist Rimonabant o Treats obesity and nicotine addiction o Many widerange effects o Withdrawn due to increase in suicide and suicidal thoughts Nicotine Primary psychoactive and addictive drug in tobacco Affects nicotinic (acetylcholine) receptors Periphery o Activates muscles and causes twitching CNS o Increases alertness and decreases reaction time o Activates nicotinic ACh receptors in the ventral tegmental area (DA) Smoking/health risk o Health risk is mostly due to other compounds in tobacco, not nicotine But nicotine is the addictive component o Smoking is the primary cause of preventable death in the world Kills 500,000/year in the US (heroin kills 400/year in US) o Withdrawal symptoms are mild o Only 5% of attempts to stop are successful; about the same statistic for heroin Cocaine Leaves from coca shrub alleviate hunger, enhance endurance and sense of wellbeing o The leaves are not addictive Cocaine, the purified extract o Crack cocaine enters the brain more rapidly o Faster speed of onset = bigger high but not as long lasting (rapid offset) highly addictive Cocaine blocks monoamine transporters, especially dopamine o Blocks reuptake of catecholamines, enhancing their effects o More serotonin, dopamine, and norepinephrine in the synaptic cleft Cocaineamphetamineregulated transcript (CART) peptide involved in pleasure sensations from these drugs and in appetite suppression o Side effect of Adderall = can’t gain weight o Goal to make an appetite suppressant that doesn’t cause addiction Cocaine increased stimulation; over short time (10 days) the brain “gives up” and see very reduced activity in the brain Amphetamine Amphetamine and methamphetamine are synthetic stimulants o Crystal meth, dextroamphetamine (slow/controlled release form) They block reuptake and increase the release of catecholamines Shortterm effects include alertness, euphoria and stamina Longterm abuse leads to sleeplessness, weight loss, and schizophrenic symptoms Stimulants for ADHD Adderall (dextroamphetamine); Ritalin (methylphenidate); Strattera (atomoxetine) Brain imaging studies show that stimulant medication increases activity in prefrontal cortex, some subcortical regions, and cerebellum all centers for executive function Corticothalamic networks control inhibitory attentional and impulse control systems and process internal and external stimuli o ADHD medications stimulate these inhibitory networks to function better Hyperactive behavior (leg tapping, fidgeting) stimulates those brain networks to work better o When the medication stimulates these networks, the hyperactive behavior becomes unnecessary and is reduced LSD Resembles serotonin Not addictive Increases activity in the visual cortex Effects o Unpredictable depend on amount taken, the user’s personality, mood and expectations, and surroundings in which the drug is used o Include dilated pupils, higher body temperature, increased heart rate and blood pressure, sweating, loss of appetite, sleeplessness, dry mouth, and tremors o May feel several different emotions or change quickly from one emotion to another o Produces delusions and visual illusions o Sense of time and self changes o Sensations seem to “cross over,” giving the user the feeling of hearing colors and seeing sounds PCP (phencyclidine) Glutamate NMDA receptor antagonist PCP produces feeling of depersonalization and detachment from reality o bizarre injuries; false sense of being able to do things that aren’t possible Its many side effects include combativeness and catatonia (can’t move/speak) Ecstasy (MDMA) Amphetamine analog/derivative o Less potent than amphetamine Primary effects in brain are on neurons that use serotonin MDMA blocks the serotonin reuptake transporter o prolonged serotonin signal excessive release of serotonin o oxytocin release Mothers naturally make oxycontin after giving birth – bonding to child Social bonding drug raves Khat Native to East Africa/Arabian Peninsula cultural tradition for many social situations Flowering shrub abused for its stimulantlike effect 2 active ingredients: cathine and cathinones Effects are similar to other stimulants, such as cocaine and amphetamine “Bath salts” “Bath salts” describes a family of manmade chemicals related to cathinone Usage is stable at about 1% of high school juniors and seniors As governments outlaw each current “bath salt” chemical, chemists synthesize new ones GHB (Gammahydroxybutyric acid) = the generic drug oxybate (FDAapproved medication = Xyrem) Used to treat narcolepsy Analogues are available legally as industrial solvents At bars or rave parties, GHB is sold in liquid by the capful for $5 to $25 GHB and its analogues increase libido, suggestibility, passivity, and cause amnesia users are vulnerable to sexual assault (daterape drug) Rohypnol = flunitrazepam Not made in the U.S. “Not trending” – old version of the daterape drug The tablet can be swallowed whole, crushed and snorted, or dissolved in liquid Adolescents abuse Rohypnol to produce euphoria Cocaine addicts use Rohypnol to relieve side effects (irritability and agitation) from cocaine binges Rohypnol is used to physically and psychologically incapacitate women for sexual assault Drugs, addiction, and reward Addiction is… o chronic o preoccupation with obtaining a drug o compulsive use of the drug in spite of adverse consequences o a high chance of relapse after quitting o Addiction can be “treated” but is not curable (debatable) o Not a shortterm by definition o Medical brain disorder o Related to how the drug is released not the drug itself Rapid onset and offset are more addictive Although the initial decision to take drugs is voluntary, brain changes that occur over time challenge a person’s selfcontrol and ability to resist intense impulses urging them to take drugs Tolerance v. sensitivity o Tolerance – decreased sensitivity to a drug as a result of taking it o More drugs have tolerance than sensitization o Sensitization increased sensitivity to a drug as a result taking it Dependence o Dependence is an independent concept of tolerance/sensitization o Physical dependence – caused by withdrawal symptoms (not the reason people continue to take most drugs) o Psychological dependence – compulsive and repetitive use, craving The basis for addiction is reward o Reward is the positive effect any agent (drug, food, sex, upvote) has on the user o Mesolimbocortical dopamine system is the major reward system o Abused drugs increase dopamine in the VTA (ventral tegmental area) o This dopamine system underlies reward effects of drugs, food, sex, gambling, etc. Withdrawal o Withdrawal is a negative reaction when drug use is stopped o Addiction and withdrawal are independent o Most addicts never get to the point of withdrawal o Rats will selfinject morphine into the VTA but not periventricular gray Indicates that VTA (but not periventricular gray) is involved in addiction o Blocking opiate receptors in periventricular gray once addicted (but not VTA) produces withdrawal Periventricular gray but not VTA involved in withdrawal Drug rehab and craving Cocaine addicts o delta FosB slowly builds up in neurons with each drug exposure and remains activated for years after the last exposure Craving still almost as strong after not having drug for 2 years o delta FosB causes structural changes in nucleus accumbens Perpetuates craving and maybe the high relapse rate in treated addicts o Drugs activate a receptor which activates delta FosB which changes transcription Change in DNA transcription = change in neuron Actual change in brain structure that does not go away Pharmacologic treatment strategies o Psychological treatment is more useful than any of the pharmacologic strategies o 1) Agonistic treatments mimic the drug’s effects, but are milder Replace the drug, which helps with motivation Methadone or buprenorphine for opiate addiction Nicotine patch Chantix stimulates nicotine receptors more weakly than nicotine does (partial agonist) – not very effective but easy to do Controversy: is it wrong to give an addict another addictive drug as treatment? o 2) Antagonistic treatments block drug effects Opiate addiction naltrexone Alcohol addiction baclofen interferes with the dopamine pathway to block craving Antagonistic treatments don’t replace the drug, so compliance depends on addict’s motivation to quit These drugs make the craving worse o 3) Aversive treatments cause unpleasant reactions when the drug is used Antabuse for alcohol addiction – when alcohol is ingested you get sick Usually just quit taking antabuse The future? Antidrug vaccines o Antidrug vaccines stimulate the immune system to make antibodies that degrade the drug (ex: nicotine) o Administered via injection o Prompts the body to make antibodies that bind to nicotine molecules o The antibodies are too big to cross into the brain, keeping nicotine away from receptors o Developed but not used – the public won’t accept it Case studies Case: Sheila Sheila fell and cut her leg; taken to local ER where the wound was cleaned and stitched Had to seek further help 3 days later when her face began to ache and she had difficulty opening her mouth. She looked unwell and complained of diffuse pain. Condition worsened 24 hours later she developed jaw stiffness, and severe back and limb spasms. Transferred to ICU. o Opisthotonos – severe muscle spasms that cause the back to severely arch Gave curare to paralyze her to protect her back She also couldn’t breathe though because the curare paralyzed the respiratory system Also gave benzodiazepine – to wipe out the memory – to relax her so she’s not aware Diagnosis: Tetanus Tetanospasmin binds irreversible to membrane at synapse, blocking release of glycine from axon terminals, causing generalized rigidity Tetanus binds irreversibly to glycine receptors, block an inhibitor = excessive excitation Symptoms from impaired glycine activity Have to make brand new receptors to cure Case: Don Developed a tremor and slowing of movements and was diagnosed with Parkinson’s disease at age 67 Was prescribed levodopa to restore dopamine levels A couple of years later, motor symptoms start to fluctuate and the dopamine receptor agonist ropinirole was added to his treatment. A few months later, he developed a strong interest in gambling. He concealed his gambling activity until he has lost more than $100,000. Came for a consultation and ropinirole was replaced with a monoamine oxidase inhibitor drug Now reports his interest in gambling has disappeared Case: Tre 5 y/o boy Mild trauma – walked into or hit by car going slowly; wasn’t knocked out Developed bump on head but cried for an hour so taken to hospital Wasn’t answering questions like he normally does Later that night, went into coma and died at that morning MRI showed brain full of water on the outside; neurons becoming waterlogged Excitotoxicity – neurons began to fire repeatedly, accumulated water; brain pressure began to rise; could not be resolved death o Neurons that fire too much kill themselves Could have given him a glutamate inhibitor but they’re not clinically safe because the brain needs glutamate for memory Shunt could have drained water but it wouldn’t have helped because the neurons were still dying Case (didn’t cover in class) 3 year old identical twins from London had severely low muscle tone, mental retardation, and seizures Biochemical analysis of CSF revealed low activity of tyrosine hydroxylase Dopamine infusions temporarily improved their symptoms Case: alcohol withdraw OJ is a 45 yo man who presents to the ER after a seizure during his first day at a local alcohol/drug rehab center About 60 hours since last drink) The seizure (tonicclonic) lasted approximately 1 minute, and resolved spontaneously Case: oxycontin 53 y/o man found on ground On exam – comatose; pupils are tiny (2mm) and barely react to light Given naloxone (opiate antagonist) via IV Within a minute he arouses and opens his eyes Diagnosis? Oxycontin overdose High death among adults (40s/50s) Possibly decreased mechanism of defense against opiates Case: addiction 24yearold man depression and OCD Electrodes implanted near the MFB which produces pleasurable sensations 3 months pass When given free access to the stimulator, he quickly began mashing the button Stimulated himself to a point that, behaviorally and introspectively, he was experiencing an almost overwhelming euphoria and elation and had to be disconnected despite his vigorous protests
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