Exam 3 Review PDF

14 Treatment of Major Depressive Disorder (MDD) (lasting weeks/months) MDD symptoms: - Sadness - Helplessnesss - Worthlessness - Impaired sleep - Impaired concentration - Anhedonia - Physical pain Multiple symptoms, must inhibit everyday life What’s wrong with the Depre...

14 Treatment of Major Depressive Disorder (MDD) (lasting weeks/months) MDD symptoms: - Sadness - Helplessnesss - Worthlessness - Impaired sleep - Impaired concentration - Anhedonia - Physical pain Multiple symptoms, must inhibit everyday life What’s wrong with the Depressed Brain? Chemical differences Cortisol (high levels → negative effects on cells (brain cells), cortisol impacts plasticity) - Dexamethasone suppression test Brain derived neurotrophic factor (BDNF) - Depression is associated w/ low BDNF in blood Inflammation → aspect of immune system that gets disregulated; high levevls of inflammation correlated with MDD Neurology of Depressed Brain 1. Structural differences - Increased cortisol, decreased BDNF 2. Decreased dendritic branching – PFC, hippocampus, amygdala - Can decrease the volume of a structure (decrease plasticity) 3. Decreased hippocampus; neurogenesis (birth of new cells) 4. Neurogenic hypothesis of depression Decreased dendritic branching + decreased cell birth = decreased volume & decreased ability ot regulate HPA = DECREASED PLASTICITY The above is normalized by antidepressant treatment Antidepressants Electroconvulsive Therapy (ECT) - Goal: induce seizures via application of electricity to the brain; forces brain to reboot - Positives: Fast Acting and effective - Negatives: effect is short-lived, treatment is time consuming, memory loss Tricyclics (late 1950s) Ex: imipramine (Tofranil) Name refers to chemical structures (shaped like a tricycle) Originally developed as antipsychptics - Positives: Block reuptake of serotonin and norepinephrine - Negative: Block Ach, histamine and epinephrine receptors Effective but undesirable side effects: confusion, memory impairment, sedation, cardiotoxic in overdose Active metabolites → clinical effect up to 4 days (longer in elderly, who are particularly vulnerable to cognitive side effects) “Gold standard” against which efficacy of new antidepressants is judged Monoamine Oxidase Inhibitors (late 1950s) Originally developed to treat tuberculosis - Positives: inhibit activity of MAO either irreversibly or reversibly - Negatives: MAO metabolizes tyramine Effective, but undesirable side effects: potentially cardiotoxic if Dietary restrictions are not followed and if adrenaline-like drugs are used (eg. antiasthma medications) Can be effective in patients unresponsitve to TCAs and SSRIs Ex. Selegiline transdermal patch (Emsam) Selective Serotonin Reuptake Inhibitors - Positives: inhibit SERT, w/ little effect on other monoamine transporters; no effect on post-synaptic 5-HT receptors - Negatives/undesirable side effects: “serotonin syndrome” = cognitive disturbances, ANS dysfunction, neuromuscular impairment, agitation, sexual dysfunction, SSRI discontinuation syndrome - Not as effective as older antidepressants :p Dual-Action Antidepressants (attempst to have therapeutic action of TCAs, w/out their cholingergic, histaminergic and noradrergic side effects) - Positives: target serotonin and norepinephrine reuptake - Venlafaxine (Effexor), active metabolite desvenlafaxine (Pristiq) - Negative/Undesirable Side effects: Sexual, blood pressure - Duloxetine (Cymbalta); approved to treat chronic neuropathic pain (fibromyalgia, diabetic neuropathy) Monoamine Hypothesis Other mechanisms of action of monoaminergic antidepressants 1. Increase BDNF → increases dendritic branching → increases #4 2. Decrease oxidative stress 3. Increase allopreganolone 4. Increase hippocampal neurogenesis ENHANCE NEUROPLASTICITY! Future of Antidepressant Treatment Why are new antidepressants needed? - Faster onset of therapeutic effect - Better efficacy - Fewer Side effects NMDA receptor antagonists - Cause burst of glutamate that stimulates synaptic plasticity Anti-inflammatory drugs 15 Pain & Opioids Pain Pathways Where is the pain? Free nerve endings → spinal cord → thalamus → somatosensory cortex How do I feel about the pain? Free nerve ending → spinal cord → thalamus → hippocampus, amygdala, cingulate cortex Pain Descending Anti-Pain Pathways - Opiates enhance this effect Pain Opportunities to decrease pain with drugs Decrease inflammation → aspirin and other NSAIDS Decrease nociceptor excitation → gabapentin & pregabalin Decrease release of neurotransmitter by cociceptor → opioids Activate anti-pain pathways → antidepressants & opioids Influence cognitive and emotional processing → opioids Terminology Opium = juice of the poppy Narcotic = any drug that induces sleep Opiate = drug extracted from opium Morphine and codeine Opioid = endogenous ligand that binds opioid receptors - Endorphins, enkephalins, dynorphins “Opioid” is now used to refer to all drugs (natural and synthetic) that target opioid receptors Opiates -> Source - Opium found in papaver somniferum - Native to Eurasia - Used for ~7000 years - Alcohol + opiun = laudanum - Hypodermic (1856) led to “soldiers disease” Opioids (Ex. enkephalin) Functions - Analgesia - Sleeo - Anti-tussive - Regulate intestinal motility (in periphery) Synthesis - Made from precurso polypeptides - Cleaved by proteases (enzymes) into active form - POMC → Endorphin - Proenkephalin → Enkephalin - Proendorphin → Endorphin, Dynorphin Receptors = metabotropic Spinal cord, brainstem (respiration), thalamusm basal ganglia, nucleus acc, cortex MU, KAPPA, DELTA Endogenous Ligand Endorphin Dynorphin Enkephalin Exogenous Ligand Morphine Salvinorin A ***Kratom Naloxone* **pentazocine **weak mu agonist ***partial Mu agonist Effects Analgesia, Euphoria Analgesia, Dysphoria Analgesia, Affect Opioid Drugs Pure Agonists (mu) - Ex. Morphine, codeine Heroin Methadone, Meperidine (Demerol) Fentanyl and its derivatives are 80-500x as potent as morphine Mu antagonists Naloxone (Narcan) Used to reverse overdose Naltrexone (ReVia, Trexan) Used for treatment – renders heroin ineffective Partial Mu Agonists Partial agonism limits respiratory depression and abuse potential Buprenorphine (subutex) Tramadol (Ultram) Blocks reuptake of norepinephrine, releases serotonin Active metabolite extends analgesic effects Mixed Agonist - Antagonists Weak Mu + Kappa Agonists Pentazocine (Talwin) Analgesic, but dysphoria limits usefulness Mixed Agonist - Antagonists Pt. 2 Partial Mu agonist + Pure Mu Antagonist Suboxone = buprenorphine + naloxone If administered orally, naloxone is inactive, but if crushed and injected, naloxone is active 16 Sleep and Insomnia Wakefulness Level of Wakefulness is determined by the relative activity of EXCITATORY and INHIBITORY chemicals Neural Control of Wakefulness Reticular Formation - Releases GLUTAMATE in the forebrain Basal Forebrain - Releases ACETYLCHOLINE in the forebrain Locus Coeruleus - Releases NOREPINEPHRINE in the forebrain HYPOTHALAMUS - Encephalitis lethargica - Cell loss in Posterior Hypothalamus [and reticular formation] - Important for Waking - Fatal Familia Insomnia - Cell loss in anterior hypothalamus - Important for Sleep Releases histamine and orexin to the forebrain - Loss of orexin-producing neurons in the hypothalamus causes narcolepsy Suprachiasmatic nucleus (SCN) = the brain’s “clock” - Controls release of melatonin by the pineal gland Releases GABA onto neurons that produce acetylcholine and norepinephrine Caffeine Adenosine receptor antagonist Adenosine is a neuromodulator that suppresses the activity of dopamine, norepinephrine, glutamate, and acetylcholine and enhances the activity of GABA Adenosine is a byproduct of energy production, so accumulates during daytime activity Cup of Coffee ~ 100 mg Can on Soda = 40 mg Lethal dose of caffeine: 10 g Metabolized by CYP-IA2 [inhibited by some SSRIs] Half life ~ 4 hr Active metabolites theophylline and paraxanthine extend effects Constricts cerebral vessel = helps w/ headache Coffee consumption is protective against type 2 diabetes, cancer, parkinson’s, alzheimer’s, cardiovascular disease, improves memory BUT!! Exacerbates anxiety Sleep Stages Awake EEG is highly variable EEG becomes progressively more rhythmic during stages 1-4 Stages 3-4 = “Slow wave sleep” Sleep is NOT the absence of brain activity! As you move through the stages of sleep, it gets more rhythmic bc the cortex acts alone??? Hypothalumus stops sending signals to cortex REM! - Tied to body temperature - REM deprivation causes REM rebound - Some drugs (Barbiturates, ALC) suppress REM - HIGHER body temp, MORE REM INSOMNIA Highly comorbid with anxiety Onset, maintenance, termination Body temperature falling = fall asleep Body temperature rising = wake up Sleep Aids Most OTC sleep aids are ANTI-histamines For insomnia → “Z drugs” = Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta) NBZRA (non benzodiazepine receptor agonist) hypnotics Half life is shorter than a full night’s sleep: 1-6 hours (zaleplon has a half life of about an hour) (ezcopiclone has a half life of about six hours) Bind 1-2 GABA receptor subunits, rather than all 5 produce amnesic state Ramelton (Rozerem) melatonin agonist, Questionable efficacy. Oxerin Receptor Antagonists Oxerin = peptide neurotransmitter 2 receptor subtypes, OX1R and OX2R Regulates transition between sleep and wakefulness by turning on arousal systems Antagonists prevent activation of arousal systems Suvorexant (Belsomra) 17 Psychedelics Anticholinergic Scopolamine - Muscarinic (mAch) antagonist Low: Sedation, mild euphoria, amnesia High: Euphoria, Hallucinations, Excitement Peripheral: tachycardia, inc. body temp, dry mouth Used for twilight anesthesia Serotonergic Chemically similar to serotonin Lysergic Acid diethylamide (LSD) Syntehtic derivative of ergot 1930s: developed to explore therapeutic possibilities [eg. vasoconstriction] 1950s: model of psychosis? Tried as an adjunct to psychotherapy Binds 5-HT2A receptors in prefrontal and cingulate cortex Perceptual distortions: visual, auditory, space/time 1938: synthesized by Albert Hoffman 1950s-1970s: used in conjunction with psychotherapy; used by military as a possible “brainwashing” drug; antiwar protests 1968: made illegal (felony posession) Serotonergic Chemically similar to serotonin Ololiuqui - Seeds of morning glory - Psychedelic compound = lysergic acid amide - NOT the same as LSD Serotonergic Chemically similar to serotonin Bufotenine - Alternative metabolite of serotonin - Found in people with psychiatric disorders (?) - Found in the skin of toads of the genus Bufo Serotonergic Chemically similar to serotonin Psilocybin, psilocin - Found in mushrooms (SHROOMS) - Rewened interest in the use of psilocybin as an adjunct treatment for depression, PTSD, addiction and end-of-life anxiety Catecholamine-like Chemically similar to norepinephrine and dopamine Mescaline Anxiety, visual distortion, tremor Synthetic methoxylated amphetamine derivatives DOM, MDA, DMA, MDE, TMA, AMT, & MDMA Increase release/inhibit reuptake of monoamines & acetylcholine MDMA - 1914: developed for appetite suppression - 1950s: US military tested it as a “brainwashing” drug - 1970s: interest in use as psychological treatment - 1980s: developed a following among college students that continues today Empathy, insight, enhanced communication and transcendent religious experiences Sympathomimetic effects, anxiety, malignant hyperthermia neurotoxic? Antiglutamatergic Phencyclidine (PCP) & Ketamine NMDA receptor antagonists - Confusion, altered perception, stupor, coma Originally developed as safer anesthetic and analgesic agents Kappa Opioid Agonist Salvinorum A Hallucinations, dysphoria 18 The Endocannabinoid System and Cannabis Endocannabinoids Functions - Analgesia - Sensory Processing - Motor Coordination - Memory and Cognition - Appetite - Immune System Synthesis - Precursos = Arachidonic acid (a fatty acid) - Too lipid-soluble to be stored in vesicles!! - Made and released on-demand Receptors - CBI (1988) Central Nervous System - CB2 (early 90s) Periphery (Immune System) CB1(1988) → Central Nervous System Very Few Brainstem Receptors Basal Ganglia Motor Coordination Cerebellum Motor Coordination Hippocampus Memory Cortex Sensory Processing, Concentration Spinal Cord Analgesia  Hypothalamus Appetite Inactivation Uptake into neurons by endocannabinoid membrane transporter Anandamide: Broken down by fatty acid amide hydrolase (FAAH) = Postsynaptic neuron 2-AG: Broken down by monoacylglycerol lipase (MGL) = Presynaptic neuron Endocannabinoids → Synaptic Transmission Postsynaptic endocannabinoid neuron gets depolarized Endocannabinoid neuron synthesizes endocannabinoids on demand Endocannabinoids diffuse into the synapse and bind receptors on the presynaptic neuron! Inhibits release of neurotransmitter from presynaptic neuron = retrograde message Cannabis Cannabis sativa and Cannabis Indica (hemp) Native to Asia, but grown worldwide Cultivated for ~6000 years American colonies grew hemp to supply rope for English nacy Anti-cannabis propaganda began in the 1930s for political reasons Cannabis sativa ~ 400 active compounds Psychoactive - Delta-9-tetrahydrocannabinol (THC) ➔ (identified in 1964) - Non-psychoactive 1. Cannabidiol (CBD) 2. Cannabinol (CBN) Timeline 1964: active component of marijuana identified (THC) ➔ But endogenous THC remained unknown 1988: the first receptor for THC was identified (CB1) 1991: the second receptor for THC was identified (CB2) 1992: endogenous THC identified (anandamide and 2-AG) Pharmacokinetics of THC - Half life ~ 30 hours - Depot binding → “reverse tolerance” - Metabolized by liver enzymes into active metabolite 1 1- hydroxy-delta-9 THC - Inactive metabolite = carboxy-THC (urine test) Medical Uses for THC Analgesia (Sativex = THC + CBD) - Suppresses pain transmission in spinal cord - Particularly effective for pain associated with inflammatory conditions (action on CB2) Appetite Stimulation (Marinol) Cancer/AIDS Cannabinoid antagonists for appetite suppression - Rimonabant (2006) 19 Alcohol Pharmacokinetics (What body does to drugs) Absorption - Diffuses easily through all membranes - Quickly passes from GI tract into blood Distribution - Easily crosses Blood-brain barrier Metabolism (Biotransformation) ~15% metabolized by gastric alcohol dehydrogenase (in liver) - Women have less GAD than men The average person metabolizes ~10 mL 100 proof alcohol in 1 hour = “zero order metabolism” Excretion ~ 5% excreted by lungs Alcohol → Pharmacodynamics (what drugs do to body) Glutamate - Suppresses NMDA receptor function - Reduces Glutamate release - Chronic alcohol consumptin increases NMDA receptors GABA - GABA agonist - Chronic alcohol consumption decreases Cl- influx Opioids - Induces opioid release - Opioid release induces dopamine release - Endogenous opioids release induced → pain reliever, sleepy, increase intestinal motility Cannabinoid System - Stimulate production of annadamide - Anandamide → endogenous THC - “Dirty Drug” referring to ALC ALCOHOL TOLERANCE - Acute = occurs with single exposure - Metabolic - alcohol dehydrogenase increases in liver - Pharmacodynamic = NMDA receptors increase [glutamate] and Cl- influx decreases [GABA] - Behavioral Alcoholism Alcohol Use Disorder Goals of AUD Pharmacotherapy (treatment of addiction w/ drugs) “drugs w drugs” - Prevent/Treat withdrawal Seizures - Prevent Relapse - Treat comorbid conditions Prevent/Treat Withdrawal Seizures - Long-acting benzodiazepines [Diazepam] - Anticonvulsants [Lamotrigine, Topiramate] Prevent Relapse - Disulfiram [Antabuse], Calcium Carbamide [Temposil] - Inhibit Aldehyde Dehydrogenase (elongates icky effects) - Low patient compliance Prevent Relapse - Naltrexone [ReVia, Trexan] - Mu Opioid Antagonist - Better than placebo - Injection More effective(?) Treat Comorbid Conditions - MDD, PTSD - Difficult to treat Binge Drinking NIAAA: drinking that results in a BAC of 0.8 or above in 2 hours - 0.8 is not very high ↑ inflammation, oxidative stress, excitotoxicity, HPA axis activity ↓trophic support, neurogenesis - White matter track becomes smaller bc of increasing inflammation, oxidative (cellular) stress, etc. - Binging once a week still affects you neurologically - Binge drinking is often done during 4 yrs of college - Correlation between women and binge drinking 20 Addiction Opponent Process Theory Overshoot baseline bc we have a RESPONSE to A process (B process) - A process is the brain’s response to a stimulus - B process is the brain’s response to the A process - With repeated exposure to the A process, the B process INCREASES IN MAGNITUDE and becomes LONGER LASTING - B process is the opposite of A A process WEAKENS, B process STRENGTHENS Opponent Process Theory Applied to Addiction - Tolerance develops as A process adapts (metabolic, pharmacodynamic, behavioral) - Withdrawal occurs as the B process becomes more prominent - B process effects are OPPOSITE to those of A - Alcohol A process = relaxation/ anxiety relief - Alcohol B process = anxiety - A process WEAKENS, B process STRENGTHENS - Drug becomes less pleasant, withdrawal and cravings dominate The Brain Disease Model of Addiction Stages of Addiction and Underlying Circuitry: Binge/Intoxication Stage - Basal Ganglia (striatum) - Reward Pathway Withdrawal/Negative Affect - Limbic system (amygdala) - Stress System (HPA axis) Preoccupation/Anticipation - Prefrontal cortex  - Stress system (HPA axis) - Insula - Basal Ganglia Binge/Intoxication Stage - Reward Pathway - Basal Ganglia (Striatum) 1. Initially, drug exposure causes dopamine release in the reward pathway ➔ Reward deficiency? ➔ Fewer D2 receptors = more pleasure from stimulants ➔ INCENTIVE SALIENCE 2. Learning occurs as associations are formed between the drug and cues that predict its availability → basal ganglia [habit formation, “autopilot”] 3. Dopamine is released in response to cues, instead of to the drug ➔ Cues invoke B process Craving result when drug-cue associations invoke the B process Withdrawal/Negative affect stage - Limbic system (amygdala) - Stress system (HPA axis) 1. “Anti-reward” or the “Dark Side” develops 2. The reward pathway becomes desensitized to reward (including natural rewards) 3. Brain stress systems and the amygdala are activated, increasing negative mood Preoccupation/Anticipation Stage - Prefrontal Cortex (PFC) - Stress system (HPA axis) - Basal Ganglia - Insula 1. Executive function impairment ➔ Hypofrontality due to drug use impairs decision-making 2. PFC is desensitized to natural rewards, but sensitized to drug cues, which worsens cravings 3. Insula is sensitive to the cravings (interoception) 4. Stress system remains active, basal ganglia autopilot remains active  Pharmacotherapy of Addiction Agonist treatments - Replace the addictive drug with another that has similar effect ➔ Methadone instead of heroin ➔ Nicotine patch instead of cigarettes Partial Agonist treatments - Prevent withdrawal and cravings w drug that offers partial effect ➔ Varenicline (Chantix) for nicotine addiction - Occupies nAch receptor (prevents withdrawal) BUT blocks nicotine’s access = makes smoking less satisfying Antagonist Treatments - Block the effects of the addictive drug ➔ Naloxone for heroin - Competitive Mu receptor agonist Aversive Treatments - Induce negative reaction when addictive drug is taken ➔ Disulfiram (Antabuse) for alcohol ➔ Suboxone (buprenoprhine + naloxone) for opioids - Naloxone is activated if Suboxone tablet is crushed and injected Antidrug Vaccines 1. Inject synthetic molecules that resemble drug 2. Immune system makes antibodies 3. Amount of drug that reaches the brain is deceased