Exam 2 Study Guide (Psychopharmacology) PDF

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Prof. Thunhorst...

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* Unit 5: Body Systems That Maintain Homeostasis * Homeostasis - Involves multiple interacting systems - Systems use negative feedback loops - Increased system activity inhibits future production Homeostasis & Control Theory: Engineering Control Theory - progressive complexity of control that can be exerted on a system - System: collection of components arranged so there is an identified output for a known input Drive-Reduction Theory - Being 1.out of sync with physiological needs leads to 2.state of drive, triggering 3.reduction behavior/response

Autonomic Nervous System 1. Sympathetic Nervous System a. Fight or Flight 2. Parasympathetic Nervous System a. Rest & Digest Autonomic Nervous System & Target Organs Cell Bodies: Sympathetic: originate in middle spinal cord Parasympathetic: originate in brain stem & lower spinal cord Neuron Chains: Sympathetic Preganglionic Nerves: - Arise from spinal cord - Synapse at chain ganglia - Postganglionic fiber extends to effector (visceral organ) Parasympathetic Preganglionic Nerves: - Arise from brainstem & sacral spinal cord - Ganglia in walls of effector organs - Preganglionic axons longer than sympathetic - Postganglionic axons shorter Similarities Between SNS and PSNS:

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Myelinated preganglionic fibers Non-myelinated postganglionic fibers More postganglionic fibers Ganglia equally susceptible to drugs Neurotransmitter at ganglia = acetylcholine Elicit denervation supersensitivity at target tissue upon removal of ganglia

Neurotransmitters in Autonomic Nervous System Sympathetic: 1. Preganglionic: acetylcholine 2. Postganglionic: norepinephrine Parasympathetic: 1. Preganglionic: acetylcholine 2. Postganglionic: acetylcholine

Pharmacology of Cholinergic Receptors 1. Muscarinic Receptors (Metabotropic) a. Muscarine = agonist b. Atropine = antagonist 2. Nicotinic Receptors (Ionotropic) a. Nicotine = agonist b. Hexamethonium = antagonist Using Ganglionic Blockers to Analyze Function Ganglionic Blockade: - Finds intrinsic level of organ activity without ANS input - Direction of change in level before & after blockade --> determine contribution of limbic system to basal activity level - Ganglion Blockers = competitive antagonist @ nicotinic receptors in autonomic ganglia - Each smooth muscle/gland has sympathetic OR parasympathetic tone - Ganglionic blocker shows which is which Alpha & Beta Adrenergic Receptors & Catecholamines Adrenergic Receptors: - G-protein coupled - Targets of catecholamines - Norepinephrine - Epinephrine

Adrenergic Alpha Receptors: 1. A1 = Gg-coupled a. A1a b. A1b c. A1d 2. A2 = Gi-coupled a. A2a b. A2b c. A2c Adrenergic Beta Receptors: 1. B1 = Gs-coupled 2. B2 = Gs and Gi - coupled 3. B3 = Gs and Gi - coupled Synthesis of Catecholamines Tyrosine → Dopa → Dopamine → Norepinephrine → Epinephrine Degradation of Catecholamines - Monoamine Oxidase (MAO) - Catechol-O-Methyltransferase (COMT) Entry of Visceral & Somatic Afferents into Spinal Cord via Dorsal Roots - Different populations of dorsal root ganglion neurons for visceral & somatic - Project to Laminae I and V of dorsal horn Visceral Afferent Information: Nucleus of Solitary Tract → preganglionic neurons in ventrolateral medulla Descending Autonomic Pathways: - Direct output to autonomic preganglionic neurons: - Arise from paraventricular & lateral hypothalamus - Less Direct Output - From cortex, amygdala, periacquaductal gray - Relayed into cell groups w/ direct input to preganglionic inputs

Endocrine Systems

Chemical Mediators: Classes: 1. Neurotransmitters 2. Hormones 3. Cytokines 4. Growth Factors Roles: 1. Polyfunctional Peptides 2. Polyfunctional Catecholamines Extracellular Chemical Communication Systems: 1. Synaptic Transmitter Communication a. Chemical Signal i. Released from terminal button ii. Binds to receptor 2. Autocrine Mechanisms a. Feedback effects (from chemical signal) on cell from which it is released i. Some synaptic transmitters are also autocrine signals 3. Paracrine Communication a. Chemical signals diffuse through extracellular space to nearby target cells i. Nearest cells = strongest effects 4. Endocrine Glands a. Produce chemical signals and release them into bloodstream i. Effects wherever hormone’s receptors are found 5. Pheromones a. Message from one individual within a species to another i. Mating 6. Allomones a. Communication between species 7. Neuroendocrine a. Neuron releases neurotransmitter into blood for circulation

Glands of the Endocrine System Gland releases a hormone which has a function Endocrine vs. Exocrine Cells: 1. Endocrine: secrete endocrine hormones into bloodstream to travel to organs 2. Exocrine: secrete products into ducts which carry them to target organ or external environment

Chemical Classes of Hormones: 1. Amine 2. Peptide 3. Protein 4. Steroid Mechanisms by Which Hormones Alter Cell Function: 1. Amino-Acid & Polypeptide Hormones: a. Interact w/ cell surface receptors i. Stimulates intracellular production of cyclic AMP 1. Binds to intracellular receptor & stimulates phosphorylation of intracellular proteins 2. Steroid Hormones a. Enter target cell & bind to specific cytoplasmic receptor i. Hormone-receptor complex transported into nucleus 1. Binds to specific sites on DNA, activates RNA Transcription

The Immune System Injury & Inflammation The Inflammatory Response: - Tissue damage allows bacteria in - Signals damage to body - Phagocytes ingest/destroy bacteria The Acute-Phase Response: - Liver produces acute-phase proteins - Bind to surface of bacteria to ‘mark’ them for phagocytes The Complement System - Plasma proteins cascade to attack/kill pathogens Phagocytosis & Antigen Presentation - Phagocytes ingest invader & create phagosome - Phagosome merges w/ lysosome to create phagolysosome

Natural Killers Cells - More specialized - Identify cells infected by virus/tumorous cells The Adaptive Immune System - Used when innate immune system = unsuccessful - Slower but more accurate - More efficient when pathogen is known - Produces memory cells - Long-term protection against infection

The Lymphatic System -

Returns lymph toward heart Lymph contains lymphocytes 1. T-Lymphocytes: - Responsible for special defense in tissue - Produced in bone marrow - Mature in thymus gland - Surface receptors bind to recognized pathogens - Pathogen that fits causes T-Lymphocytes to quickly multiply 2. B-Lymphocytes: - Produced AND mature in bone marrow

Cytokines - Small proteins which signal other cells to affect their function - Can be pro-inflammatory or anti-inflammatory Microglia - The brain’s immune mechanism - When activated, secrete destructive molecules & become phagocytes

* Unit 6: Research Methods in Psychopharmacology * Behavior Studies Used in:

1. Behavior Analysis 2. Drug Development 3. Animal Models of Disease 4. Behavioral Phenotyping Uses in Pharmacology: 1. Drug’s effects on psychological processes? 2. Behavioral changes w/ drug? 3. Therapeutic potential? 4. Toxic Effects? Classes of Behavior Studied in Psychopharmacology: 1. Simple (no training required) a. Reflexes b. instinctive/motivated behavior 2. Complex (training required) a. Learned behavior Simple Behavior Tests: 1. Tail-Flick Test = Withdrawal Reflex 2. Open Field Test, Activity Cages, Swimming, Running Wheel, Rotarod = Locomotor Tests Complex Behavior Tests: 1. Thorndike’s Puzzle Box (Instrumental Conditioning) a. Behavior & Consequence

Animal Models of Disease Why use them? - Precision of control over experimental variables - Life history/heredity control - Isolation of causes - Continuous monitoring - Lab disorder vs. natural disorder - Mechanisms of disease - Etiology & progression - Therapeutic strategies/agents - Preventative interventions, drug development & screening - Genetic/epigenetic manipulation - Behavioral phenotyping

Behavioral Methods in Integrative Physiology & Pharmacology Behavioral Assays: actions of drugs - High predictive validity → powerful drug screens - Homologous models of psychological disorders → cause/progression - Animal model depends on purpose - Consider labor-intensity Complexity of Modeling Psychological DIsorders: - Simple disorders/syndromes - Signs vs. Symptoms - Objective vs. Subjective - Physiological Disorders - Signs - Psychological Disorders - Few signs - Many symptoms Symptoms and Signs of Major Depression: Must Have At Least One: 1. Depressed mood 2. Loss of ability to experience pleasure Must Have At Least Five: 1. Worthlessness/guilt 2. Diminished concentration 3. Thoughts of death/suicide 4. Weight change 5. Sleep disturbance 6. Psychomotor agitation 7. Fatigue/loss of energy Animal Models; Validity & Reliability Validity: - ideas/concepts = true - Research conducted correctly - ‘X truly measures X’ - Types: 1. Predictive Validity - Most important for drug screening

- May lack face validity 2. Face Validity - Model resembles condition (homologous) 3. Construct Validity - Measures = theoretically relevant Reliability: - Measure = consistent and reproducible - Minimal error Animal Models; Disorders Studied Pain Motor Disorders Eating Disorders Dementia Anxiety Depression Schizophrenia How to pick a model? 1. Goal a. Drug/therapeutic screening b. Cause c. Mechanisms of course 2. Resources/Cost Animal Models; Anxiety 1. Open Field Behavior 2. Light Avoidance 3. Conditioned Defensive Burying 4. Elevated-Plus Maze 5. Response Suppression a. Unconditioned behaviors (licking) b. Conditioned behaviors c. Effective dose for rat vs. clinical dose for humans Animal Models; Depression - Have high predictive validity - Have low face & construct validity - Model Types: 1. Muricide a. Rats killing mice 2. Differential Reinforcement of Low Response Rates (DRL)

a. DRL-72s i. Reduced response rate ii. Increased reinforcement iii. Patience 1. Rat must wait 72s between bar press to receive reinforcement a. Antidepressants → increased patience 3. Porsolt Forced Swim Test of Behavioral Despair (Homologous Model) a. Day 1: 15min forced swim b. Next 24 hrs: vehicle/antidepressant c. Day 2: 5min forced swim i. Measure duration of active swimming vs floating 4. Chronic Mild Stress-Induced Anhedonia (Homologous Model) a. Behavioral Measures: i. Ingestion of palatable liquids ii. Instrumental responding for rewarding stimuli b. CMS Protocol i. Mildly stressful situations 1. Lighting 2. food/water deprivation ii. Normal water vs. tasty drink 1. Control animals vs. stressed animals Animal Models; Schizophrenia Animal Assay 1. Paw Test (Antipsychotics) a. Time taken to remove limbs from holes Homologous 2. Prepulse Inhibition a. Startle response b. PPI = reduced startle when low intensity stimulus introduced before intense stimulus i. Drugs tested for ability to restore PPI response

Neuropharmacology/Neuroscience Methods Visualizing the Brain Tissue/Cells

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Tissue = ‘fixed’ Electron microscopic

1. Postmortem Examination a. Anatomical level 2. Autoradiography a. x-ray/nuclear emulsion i. Track decay emissions from radioactive substance b. Film opposed to tissue section to make autoradiograph 3. Immunocytochemistry a. Anatomically locate protein/antigen using antibody that binds to it i. Fluorescence microscope b. Inject animals w/ protein i. Stimulates secondary immune response 1. Isolate antibodies from serum 4. In Situ Hybridization a. Localization of nucleic acid within histologic section i. Thru applying complementary strand of nucleic acid 5. X-Ray a. X Radiation i. Shows tissue density 6. Electroencephalograph (EEG) a. X-Ray photo of brain after replacing CSF w/ air or oxygen i. Shows brain cavities clearly 7. Internal Carotid Arteriogram a. Visualize inside of blood vessels and organs i. Inject radiopaque contrast medium & take x-ray 8. Computer-Assisted Tomography (CT) a. 2D & 3D imaging b. CAT Scan i. Many x-ray photos combined 9. Positron Emission Tomography (PET) a. Inject fast-decaying radioactive substance to bloodstream i. Decay produces photons ii. Locate parts of brain that use decayed substance (oxygen) 1. Damaged areas → less oxygen 10. Magnetic Resonance Imaging (MRI) a. Calculates electrical charge to locate spinning atoms b. fMRI i. Regional differences in activity

1. Activity → more oxygen → more blood flow → oxygenated vs. non-oxygenated blood Manipulating the Brain 1. Stereotaxic Surgery a. Stereotactic instrument finds landmark on skull & coordinates map i. Determines where to drill hole 2. Ablation & Lesions a. Tube sucks up parts of brain i. Electrolytic Lesions 1. Pass electrolytic current thru tip of electrode a. Destroys surrounding tissue ii. Excitotoxic Lesions 1. Inject small volumes of excitatory substances into area a. Cells become overactive & die i. Cell bodies destroyed, fibers in tact iii. Antisense RNA 1. Prevent translation of RNA into proteins iv. Stimulation 1. Electrical 2. Chemical a. Microdialysis i. Continuous measurement of chemical concentrations in extracellular fluid b. Chemical Assay i. Physical detection of amount of substance c. Radioimmunoassay

* Unit 7: Psychostimulants * Sleep/Wake Cycle Changes in Arousal - Changes in neural activity 1. Systems: control rhythmic changes 2. Cells: Neurotransmitters & drugs affect cell activity

Frequencies of Physiological Responses & Behaviors 1. Ultradian Rhythms ( Barbiturates: - Safer - Higher therapeutic index - Lower chance of respiratory depression - Less enzyme induction - Slower tolerance development - Lower risk of physical dependance - Less depression of REM sleep Benzodiazepine Therapeutic Uses: 1. Chlordiazepoxide a. Anti-convulsant b. Muscle relaxer c. sedative/hypnotic d. Treats: i. Prolonged anxiety

2. Diazepam (Valium) a. Anti-convulsant b. Treats: i. Status epilepticus c. Used in dental surgery, acute alcohol withdrawal 3. Oxazepam a. Metabolite of Diazepam Benzodiazepine Problems/Concerns: - Tolerance, dependence, cross tolerance all common - BUT rarely serious consequences Benzodiazepine Metabolism: Two-Phases: 1. Phase I: creation of active metabolites in liver 2. Phase II: conjugation w glucoronide & formation of watersoluble inactive metabolites for excretion Benzodiazepines & GABAa Receptor Complex: - Benzos enhance GABA activity at allosteric receptor sites - CANNOT open channels w/o GABA present - Barbiturates can open channels directly & for longer time Non-Barbiturates & Non-Benzodiazepines 1. Chloral Hydrate a. Reduced to active metabolite in liver b. Used as pre-medication for kids/the elderly 2. Carbamates (Meprobamate) a. Muscle relaxer b. Habituation & physical dependence similar to barbiturates 3. Buspirone a. Treats anxiety b. 5-HT receptor agonist c. No anti-convulsant properties Ethanol/Alcohol 1. Effects @ GABA Receptor a. Mimics GABA i. Binds to inhibit neural activity 2. Effects @ Glutamate Synapse a. Two Ways:

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Inhibits NMDA Receptors 1. Channels don’t fully open a. Less sodium & calcium enter → less excitation Increases activity of Presynaptic Metabotropic Glutamate Receptors 1. Decreases release of Glutamate

Alcohol Time Course of Concentration: - Concentration higher in brain than blood shortly after administration Alcohol Metabolism: - Ethanol oxidated by alcohol dehydrogenase - By using NAD+ to form acetaldelhyde - Acetaldehyde → acetic acid → CO2 & H2O...