Exam 4 - Final Review PDF

Neuropharmacology – Intro. To Neuroscience Lecture Looking more into synapses and neural communication. Topics outlined are REVIEW! from the review! Types of neurotransmitters Amino Acid Neurotransmitters GABA –...

Neuropharmacology – Intro. To Neuroscience Lecture Looking more into synapses and neural communication. Topics outlined are REVIEW! from the review! Types of neurotransmitters Amino Acid Neurotransmitters GABA – MOST widespread INHIBITORY transmitters. Glutamate – MOST widespread excitatory transmitters. Peptide Neurotransmitters (neuropeptides) Opioid peptides (endorphins) Oxytocin, vasopressin Amine Neurotransmitters Acetylcholine, dopamine, serotonin Gas neurotransmitters Serves as retrograde transmitters. Examples: nitric oxide and carbon monoxide Lipid Neurotransmitters Endocannabinoids ALSO retrograde Neurotransmitter Pathways in the Brain Cholinergic – Basal forebrain to cortex, amygdala, and hippocampus Dopaminergic - Mesolimbocortical pathway to Ventral Tegmental Area (VTA) and Mesostriatal pathway – substantia nigra to basal ganglia Noradrenergic - Locus coeruleus to Forebrain and Lateral Tegmental Area - Brain stream and Spinal cord Serotonergic – Midbrain raphe nuclei to forebrain; brainstem raphe nuclei to spinal cord. LOCKS = RECEPTORS KEYS = LIGANDS Ligands include ENDOGENOUS neurotransmitters and hormones or EXOGENOUS drugs/toxins. 75% of all drugs made act via the metabotropic receptors!! A given neurotransmitter may interact with many different receptors in different parts of the brain. Ionotropic-direct A neurotransmitter may activate an IONOTROPIC receptor at some synapses, opening an ion channel to affect the postsynaptic cell’s membrane potential. Metabotropic-indirect The same neurotransmitter may, at another synapse, activate a METABOTROPIC receptor, which activates SECOND MESSANGES (via G proteins) that open other ion channels, and/or cause other changes to the cell. Types of Drugs A drug is any substance that when administered produces a BIOLOGICAL effect/change. Agonist mimic or enhances a neurotransmitter’s ability. Can be partial or full. Initiates normal effects of the receptor. A PARTIAL agonist has LESS of an effect than the endogenous ligand would have. Antagonists may REDUCE release or a neurotransmitter or BLOCK receptors. STOP/AGAINST. Can be competitive or noncompetitive. Prevents a receptor from being activated by other ligands. Neuromodulators indirectly affect transmitter release or receptor response. Acetylcholine (Ach) is the neurotransmitter released at the NEUROMUSCULAR JUNCTION binding on the muscle. TWO TYPES! 1) Nicotinic Most are ionotropic, excitatory, and peripheral. 2) Muscarinic Most are metabotropic, excitatory/inhibitory, and act on CNS. Drugs effects can be Presynaptic and/or Postsynaptic. *Count the Ways Drugs Affect Synaptic Transmission* AGO = Agonist ANT =Antagonist NT = Neurotransmitter Classes of Drugs Focus on drugs of abuse and addiction: Stimulants Opiates Cannabinoids Depressants Psychedelics Q: Benzodiazepines bind to a different spot-on GABA receptor than GABA and increase the effects of GABA w/o actually opening GABA channels, what is it? on receptors acting A: Neuromodulator ~ Simulants Nicotine is a primary psychoactive and addictive drug in tobacco. Activates ACH receptors in the ventral tegmental area (DA). In the periphery, it activates muscles and causes twitches. Centrally, it increases alertness and decreases reaction time. From 7 seconds? Smoking is a health risk mostly due to other compounds in tobacco, not nicotine. But nicotine is what makes it ADDICTIVE and therefore going back to these harmful chemicals.  Smoking is the PRIMARY cause of PREVENATABLE death in the world: Kills 493,000 ppl. A year in the US and 4 million worldwide. Heroin kills 400 ppl. A year in the US. Withdrawal symptoms are mild, but 7% in workplace accidents. Only 5% of each attempt to stop are successful, about the same static for heroin. Caffeine Adenosine is a neuromodulate that is normally released with catecholamines. Caffeine BLOCKS effects of ADENOSINE, a neuromodulator that normally INHIBITS catecholamine release via the presynaptic auto receptors. (Remember from last lecture that it’s an antagonist). Caffeine thus stimulates catecholamine release, causing arousal. ~ tiredness If Caffeine is an antagonist for adenosine, then what is a neuromodulor?? A neuromodulator are chemicals that indirectly impact neurotransmitter release or receptor response. Adenosine acts to inhibit / modulate the release of catecholamines (epinephrine, norepinephrine, and dopamine) for sleep. Caffeine binds to adenosine receptors and prevents the inhibition of catecholamines – thus more stimulation to be AWAKE!! Cocaine - Cocaine blocks monoamine transporters, especially DOPAMINE – blocking REUPTAKE of catecholamines, enchaining their effects. - Cocaine-amphetamine-regulated transcript (CART) (like mentioned before) – PEPTIDES are involved for pleasure sensations from these drugs and in appetite suppression. - Chronic cocaine use downregulates the brain metabolism, like Alzheimer’s disease.  ~ ADHD Amphetamine Amphetamine and methamphetamine are synthetic stimulants. - They block REUPTAKE & INCREASE release of catecholamines. - Short-term effects = alertness, euphoria, and stamina - Lone-term abuse = sleeplessness, weight loss, schizophrenic symptoms Amphetamine-like drugs are used to treat ADHD. Adderall – dextroamphetamine Ritalin – methylphenidate Strattera – atomoxetine Brain imaging studies show that stimulant medication increases activity in PREFRONTOAL CORTEX, some subcortical regions and cerebellum. ALL CENTERS FOR EXECTUVEI functions. Cortico-thalamic networks controls inhibitory attentional and impulse control systems and process internal & external stimuli. ADHD medications STIMAULTE INHIBITORY NETWORKS to function more effectively.  pain ! Opiate drugs bind to Opioid Receptors: Acting on many places in the Brain and Nervous System - Peptides that bind to opioid receptors and relieve pain (analgesics) ADDICTIVE. - Can depress breathing by changing neurochemical activity in brain stem, where autonomic body functions are controlled. - Opiates can change limbic system, which controls emotions, to increase feelings of pleasure. - Can block pain messages transmitted through spinal cord from the body. Endogenous are produced by the pituitary and hypothalamus during exercise, excitement, pain, eating spicy food, and love for analgesia production and feeling of well-being. Endogenous Opiates include: - Enkephalins - Endorphins - Dynorphins Opium and Morphine Opium contains morphine, a potent analgesic. Binds to opioid receptors in brainstem, especially in the LOCUS COERULEUS and the PERIQUEDUCTAL GRAY. Origin of Heroin (diamorphine) - Bayer sought a new Aspirin and Codeine replacement. Bayer marketed Heroin as a cure for codeine addiction before it quickly discovered that is rapidly metabolizes into morphine. - Was used as cough syrup and trying to help with fever and inflammation in the beginning. Cannabinoids have many Effects: Active ligands include THC (tetrahydro cannabinoid) and CBD (cannabidiol). * The brain has cannabinoid receptors that bind to ANANDAMIDE and 2-AG (2 arachidonoyl glycerol) (endocannabinoids) : Endocannabinoids are RETROGRADE signaling molecules released to activate cannabinoid receptors on nearby neurons. Lipophilic molecules, so can’t be stored in vesicles, thus exist as part of the membrane. Synthesizes “on-demand” - CB receptors are concentrated in brain areas that influences pleasure, memory, < concertation, time perception, appetite, pain, and coordination. - Impairs short-term memory – making it hard to learn complex tasks. - Slows reaction time and impairs driving. - Alters judgement and decision making. - Alters mood – euphoria, calmness in high doses, anxiety, and paranoia. Depressants Alcohol has complex effects on behavior: In low doses it is a stimulant, turning off cortical inhibition, reducing social constraints, and anxiety. At higher doses alcohol has sedative effects. Reduces brain metabolism and effects are biphasic. Variation in blood alcohol levels (BACs) - Food slows gastric emptying and absorption, and more alcohol is degraded before being absorbed. EAT! - Carbonation speeds absorption.  Differences in metabolism 1) Women have less ADH in stomach. 2) Chronic drinkers have more ADH. 3) Older people have reduced liver function and metabolism. 4) 50% of certain Asian groups have reduced ALDH function, causing an alcohol flush reaction and acetaldehyde toxicity. INHIBITS GLUTAMATE (excitatory transmitter) Acts at GABAa receptor to INCREASE binding of GABA (inhibitory transmitter) Combined effect at glutamate and GABA receptors is sedation, anxiety reduction, * muscle relaxation, inhibited cognitive and motor skills. Pleasurable effects from stimulation of dopamine, opiate, serotonin, and cannabinoid receptors. Seizures during alcohol withdrawal are due in part to COMPENSATORY INCREASE in the * number of GLUTAMATE receptors over time. Effects of Chronic Alcohol on an Adult Brain – Causes damage in cerebellum and frontal lobe. Neurons CAN recover! Fetal Alcohol Syndrome Mother’s use of alcohol during brain development: - Brain smaller and malformed with dislocated neurons. Some neurons migrate TOO far. - Cortical neurons do not migrate correctly into columns. Psychedelics - LSD resembles SEROTIN. Serotonin agonist on receptors (5-HT2A) in VISUAL CORTEX. - - Effects are unpredictable. Depends on amount taken, personality, mood, expectations, and surrounds. Effects includes DILATED pupils, high body temp., tachycardia, hypertension, sweating, loss of appetite, sleeplessness, dry mouth, and tremors. Ecstasy (MDMA) - - MDMA blocks serotonin reuptake transporter which removes serotonin from synapse. MDMA prolongs serotonin single and causes excessive release of serotonin. MDMA causes oxytocin release. - Phencyclidine (PCP) - Glutamate NMDA receptor antagonist. PCP produces feelings of depersonalization and detachment from reality. Its many side effects include combativeness and catatonia.  New Drugs Hundreds of new chemicals each year are released. - Synthetic marijuana AB-FUBINACA K2 or Spice Synthetic amphetamines Cathiones – bath salts Synthetic opiates Carfentanil produces a heroin-like high, but its 100 times more potent than fentanyl and 10,000 times more potent than morphine. Q: What class of drugs target serotonin for their primary effects? A: Psychedelics? Drug, addiction, and reward Addiction is a chronic, often relapsing brain disorder that causes compulsive drug use, despite harmful consequences to the addict and to those they are near. Although the initial choice to take drugs is voluntary, brain changes that occur over time challenge a person’s self-control and ability to resist intense impulses urging them to take drugs. Addiction is preoccupation with obtaining a drug, compulsive drug in spite of adverse consequences, and a high chance of relapse after quitting. Withdrawal is a negative reaction when taking a drug is stopped. Reward Reward is the positive effect any agent has on the user. Mesolimbocortical dopamine system is * the major reward system. Many addictive drugs cause increased dopamine production in the ventral tegmental area (VTA) which is released in nucleus accumbent through the medial foreman bundle. (REMEMBER SELF-STIMULATION) Tolerance is the decreased sensitivity to a drug as a result of taking it. - Sensitization is increased sensitivity to a drug as a result to taking it. * - Physical Dependence is caused by withdrawal symptoms (not why people continue to take most drugs) Psychological Dependence is compulsive and repetitive use, craving. und Number of receptors in a neuron varies over time. Changes rapidly during development, drug use, learning. - Up-regulation is an increase in number of receptors. SENSITIZATION Like nicotine receptors when you start smoking. - Down-regulation is a decrease. TOLERANCE Like benzodiazepines (Valium) down-regulate their receptors. Addiction & Withdrawal are independent. - Rats will self-inject morphine into VTA, indicating the area is involved in addiction. But blocking opiate receptors there does not produce withdrawal. - Rats will NOT work to inject morphine into periventricular gray, so it is not involved in addiction! But once rats are addicted blocking opiate receptors in pericentriolar gray produces withdrawal. Addiction (VTA) and withdrawal (periventricular gray) are INDEPENDENT and are physically separated. * Neural Mechanism of Drug Reward What does Dopamine do?? - Dopamine doesn’t not equal pleasure!!! - Pleasure involves endogenous opioids and cannabinoids released in the brain. - Dopamine is involved in reward, learning, motivation, and movement. “Wanting”. “Wanting” involves dopamine! - When dopamine is reduced, animals will not work very hard to obtain reward in an operant paradigm. Why does drug rehab have a low success rate? Cocaine addicts: - Delta FosB slowly builds up in neurons with each drug exposure but remains activated for years after last exposure. - Delta FosB causes structural changes in nucleus accumbent which perpetuates craving, and perhaps the high relapse rate treated in addicts. Treatment for Addiction 1) Agnostic treatment mimic drug’s effects, but milder. - Methadone or buprenorphine for opiate addiction - Nicotine patch - Chantix stimulates nicotine receptors weaker than nicotine does (partial agonist) These replace drug, which helps with motivation. Controversy: is it wrong to give an addict another addictive drug as treatment?? 2) Antagonistic treatment block drug effects - Opiate addiction – naltrexone; Alcohol addiction – baclofen interferes with dopamine pathway to block cravings. - Antagonistic treatments DON’T replace the drug, so compliance depends on addict’s motivation quit. 3) Aversive treatment cause unpleasant reactions when drug is used. - Antabuse for alcohol addiction. Future? - Anti-drug vaccines: stimulate immune system to make antibodies that degrade the drug (nicotine).  Psychopathology – Intro. To Neuroscience The Toll of Psychiatric Disorders is Huge: - About 19% of adults in U.S. suffer from psychiatric symptoms a year. - 46% of fall victims during a lifetime - Leading cause of disability in U.S. and Canada from those 25-44 years old. - Cost is around $467 billion/yr. in the U.S. Schizophrenia “A Baffling Mind” Definition: UNDERACTVITY of temporal and frontal lobes– “hypo frontality” hypothesis. - Affects 1% of the population. - Partly heritable - Patients are typically diagnosed in young adulthood, commonly 26 years old. - Dissociative thinking or impaired logical thought is the key symptom. It has an unusual array of symptoms: Positive are abnormal behaviors that are GAINED including hallucinations, delusion, excited moto behavior. - Usually, acute, and more likely to respond to antipsychotic medications. Negative symptoms result from LOST functions including slowed though and speech, emotional and social withdrawal, and blunted affect or emotional expression. Cognitive symptoms are changes in memory, disorganized thoughts, difficulty concentrating and following instructions. - Vulnerability: - Environmental exposures combined with a person’s genetic vulnerability and illness occurs is a threshold is exceeded. - Environmental factors upregulate and downregulate gene function. A fundamental characteristic of epigenetics is that the same genome cah have different phenotypes. denvinomet sever & Winter Birth Effect - Some brain defects in schizophrenia apparently stem from environmental problems during pregnancy or at the time of birth. - Month/timing in the year has been traced back into the average of schizophrenic diagnosis later in life. Q: Which is does not show the importance of environment on schizophrenia? A: The fact that the twin rate is only 50%? Pyramidal cells in HIPPOCAMPUS are DISORGANIZED in schizophrenia. + Hippocampus & Amygdala are SMALLER in some schizophrenics. + Have a deficiency of Reelin “stop” signal for migrating cells, particularly in hippocampus and prefrontal areas. ↓ D Accelerated Loss of Gray Matter in Teens w/ Schizophrenia - Some studies show loss of gray matter and less metabolic activity in frontal and temporal lobes. * Antipsychotic (neuroleptic) drugs – Class of drugs to treat schizophrenia and aggressive behavior. - Typical neuroleptics are dopamine (D2) antagonists. Dopamine hypothesis of schizophrenia Schizophrenia results from EXCESS synaptic dopamine or increased postsynaptic sensitivity to it. - Neuroleptics are DA antagonists. - Chronic amphetamine use produces a schizophrenia-like syndrome. - L-dope treatment for Parkinson’s may produce psychosis. - Treatment of schizophrenia with antidopamine drugs can produce Parkinson’s symptoms. - D2 levels in auditory thalamus are higher in schizophrenics. The dopamine hypothesis of schizophrenia is not the whole story. Problems with dopamine (DA) hypothesis: - Schizophrenics have normal DA metabolite levels. - Drugs block DA receptors much faster than symptoms are reduced. - Atypical antipsychotic drugs raise DA levels in some parts of the brain. - Some patients don’t improve on antidopamine drugs. Atypical neuroleptic drugs (Risperidone, Clozapine) block serotonin (5HT2) receptors as well as D2 receptors; some increase dopamine in frontal cortex. Glutamate hypothesis - SCHIZOPHRENIA IS UNDERACTVIATION OF GLUTAMATE RECEPTORS - PCP is an NMDA receptor antagonist, PREVENTING glutamate from acting normally. - When NMDA receptors are underactivation is prolonged, symptoms like acute schizophrenia emerge. - Atypical antipsychotics DECREASE glutamate REUPTAKE by downregulating glutamate transporter gene – increasing synaptic glutamate levels. & maybe ? Overactivity of endocannabinoid hypothesis - Endogenous cannabinoids act on receptors (CB1) - CB1 receptors is an inhibitory modulator of other neurotransmitters. EC levels are ELEVATED in CSF of schizophrenics – post-mortem studies show increased CB1 receptor binding.  cannabinoi ep synap o -cytoplas s Ponti G- promin Q: Which is evidence against the dopamine hypothesis? A: Atypical antipsychotics can alleviate positive symptoms with little D2 binding? Depression is the MOST Prevalent Disorder of Mood Characterized by: · - Sad mood - Feeling worthless/guilty - Low motivation - Fatigue/lack of energy - LOSS OF INTREST OR PLEASURE IN ACTVITEIS - Problems concentrating and thinking. - Increased or decreased appetite and weight - Changes in sleep - Suicidal thoughts/plans “Normal” vs. “Clinical” Normal reaction to life events, “blue” mood, few other symptoms, short duration, little if any impairment in functioning Clinical - Mood described as “black”, many symptoms, long duration, significant impairment in function. Postpartum Depression – PPD Depression before or after childbirth. 10% of women show S/S of PPD. 50% of women with PPD also have depression during pregnancy. Greatest risk factor for PPD is history of depression. Brain Activity in Patterns in Depression - Increased blood flow to orbitofrontal cortex and amygdala - Decreased blood flow to areas involving attention and language. * - Anti-Depressants - Monoamine oxidase inhibitors (MAOIs) prevent breakdowns of monoamines at the synapse. Accumulation of monoamines is the major action of antidepressants. - Follows a dopamine molecule from vesicle to its release and binding to its destruction by MAO. Modern classes of Anti-Depressants = - Tricyclics (older) – Increases norepinephrine and serotonin at synapses by blocking their reuptake into presynaptic axon terminals. - Selective serotonin reuptake inhibitors (SSRIs) like Prozac or Zoloft causes serotonin to accumulate in synapses with FEWER side effects than tricyclics. - Serotonin and noradrenaline reuptake inhibits (SNRIs) Monoamine hypothesis states that depression is due to REDUCDED synaptic activity of norepinephrine and serotonin. + MAO inactivates monoamines. Treatment with MAO inhibitors raise levels of monoamines at the synapse and improves depression. Reserpine is a drug that reduces monoamines to treat high BP and cause depression. All antidepressants appear to work via: - Inhibiting reuptake of 5-HT (serotonin) OR NE (norepinephrine) OR - Binding to PRESYNAPTIC 5-HT or NE auto receptors, thus enhancing neurotransmitter release. OR - Inhibiting monoamine oxidase, thereby reducing neurotransmitter breakdown. Neurogenesis During Antidepressant Treatment Electroconvulsive Shock Therapy - Early findings – drug -induced seizures alleviated depression. - ECT has similar effects that raises monoamine levels. - ECT increases sensitivity of postsynaptic serotonin receptors. - Sensitivity of presynaptic auto receptors is reduced, increasing norepinephrine and dopamine release. + ECT is now used in severe depression – suicidal ideation that requires immediate alleviation. Brain stimulation treatment for affective disorders - Fast TMS (transcranial magnetic stimulation) produces effects to traditional ECT. - Deep brain stimulation of the anterior gyrus and median forebrain bundle also produces immediate effects. - Stimulation of the vague nerve relieves depression, probably because it increases GABA LEVELS IN THE CORTEX. Problems with Serotonin hypothesis of depression: - Long lag time between treatment and reduction of symptoms Prozac causes locus coeruleus (NE) neurons to acquire serotonergic functions, such as SERT and serotonin synthesis. And neurogenesis takes time. - Not everyone is cured, or even helped by SSRI meds. Studies conclude that antidepressants have a 50-60% response rate in the primary care setting. - Ketamine is a new rapidly effective FDA antidepressant. + Activates glutamate AMPA receptors. ↑ ↳ NMDA-receptor Glu ketmine ↓ AMPA- & calcium receptiv Channel > ·↓ Which antidepressant should I use? - SSRI (selective serotonin reuptake inhibitors) / SNRI - TCA (tricyclics) - MAO Inhibitors - then Ketamine Clinical studies conclude that outcomes, quality of life and treatment cost provide no guidance on choice. + The reason SSRIs are used as first choice is lower severity of adverse effects and less danger with overdose. Hypothalamic-Pituitary-Adrenal Axis in Depression - Sleep is disturbed in depression! - Deep slow-wave sleep is reduced and garmented. - Patients enter REM sleep QUICKLLY, with increased REM sleep in first half of night.  Seasonal Affective Disorder - SAD - Mild depression brought on by shorter days of winter/lack of sunlight. - Phototherapy in the early morning can SUPPRESS MELATONIN and improve SAD. - SAD may also respond to SSRIs a bit. Bipolar Disorder Symptoms: Formerly “manic depression” - Periods of depression alternating with periods of expansive mood (mania) * including hyperactivity, grandiosity, extreme energy, and talkativeness. - Rate of alternation between moods varies. - Rapid cycling consists of four or more cycles per year. - 3% of U.S. Population affected each year. - Men and women are equally affected. Brain changes - Enlarged ventricles and reduced gray matter. - Similar brain changes as schizophrenia indicates bipolar disorder have more in common with schizophrenia than with depression. - Typically, the more manic episodes a person has had, the greater the ventricular enlargement. Treatment: - Lithium was discovered when trying to develop a model for mania. Reported to INCREASE GRAY MATTER in patients’ brains. Use must be carefully monitored for toxic side effects. Lithium alters second messengers from G-protein coupled receptors, which stablizes intracellular signaling. Heritability - Depression and bipolar disorder both have a strong genetic component. - Depression in identical twins is 40% concordance rate. Fraternal twins have a 20% concordance rate. - No single gene for either; many genes make people more or less susceptible and these interact with environmental factors. Cognitive behavioral therapy - Can be as effective as antidepressant medication and therapy + medication is more effective than either alone. - Therapy aims to help with recognize self-defeating modes of thinking and breaking a cycle of self-fulfilling depression.  Thoughts 1) 7 see no point in trying ~ Behavior (reduced) MOOd CION) guilty discouraged, avoidance less active < , worthless Anxiety Disorders Symptoms: - Overwhelming fear - Excessive anxiety and worry - Sense of terror - Feeling of loss of control - Physical sensations (shaking, difficulty breathing, dizzy, trembling, etc.) Disorders include: - Panic disorder - Phobia disorder - Generalized anxiety disorder Strong genetic contributions to each disorder. Tend to be associated with increased amygdala and hippocampus activity. Treatment - Benzodiazepines is a common treatment for anxiety disorders. Diazepam (valium), alprazolam (Xanax), lorazepam (Ativan), triazolam (Halcion). * + Facilitate GABAa receptors to enhance the inhibitory effects of GABA. +Act at benzodiazepine binding site om GABAa receptors is widely distributed throughout the brain. - Serotonin agonists and SSRIs are also used to treat anxiety, including Buspar (acts as 5-HT 1A receptors). - Q: Lithium is used to treat what? A: Bipolar Disorder  Learning and Memory – Intro. To Neuroscience Memory refers to the ability to store and retrieve information, or the specific information stored in the brain. - Persist after experience has ended. - Can enter latent state before being reactivated by a retrieval process. Learning is the process of acquiring new information. - Initiated by experience. - Selects the information that enters into memory by separating our relevant stimuli for retention. - We can only tell if learning has occurred if a memory is elicited later. Sensory buffer (sensory memory) are the briefest recollections of sensory impressions (