PSY 342 Exam 1 Review - Lecture notes Lectures 1 (part of), 2, 3 PDF

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Exam 1 review for Marwa Azab Psychopharmacology, Ch. 1 (parts of it), 2 , 3....

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PSY 342: Exam One Chapter 1: Principles of Pharmacology I.

Pharmacology: The Science of Drug Action a. Pharmacology: study of drug actions and their effects on living organisms. i. Specialized fields related to drugs in the pharmaceutical industry: 1. Neuropharmacology: study of drug-induced changes in nervous system cell functioning. 2. Psychopharmacology: emphasizes drug-induced changes in mood, thinking, and behavior. 3. Neuropsychopharmacology: identifies chemical substances that act on the nervous system to alter behavior using chemical agents as probes to gain understanding of the neurobiology of behavior. ii. Drug action: Molecular changes produced by a drug when it binds to target site or receptor. Drug effect: Molecular changes alter physiological or psychological function. iii. Whatever one is taking the drug for (desired physical or behavioral changes) is the therapeutic effect. Any other effect is a side effect, whether it is negative or not. 1. Specific drug effects: based on physical and biochemical interactions of a drug with a target site in living tissue (specific to the drug-target effect). 2. Non-specific drug effects: based on unique characteristics of the individual (not specific to the drug-target effect because it depends on mood, expectation, environment, perceptions). b. Placebo effect: this is a nonspecific drug effect because there is a belief. i. Can produce real physiological effects despite lack of chemical activity (therapeutic and/or side effects). ii. Example of the mind-body interaction, understanding mechanism for placebo effect may enhance the therapeutic effectiveness of drug treatments. iii. Placebos can show inexpensive treatment that avoids interactions with other medications. iv. Possible explanations for placebo effects: 1. Pavlovian conditioning (classical) 2. Conscious expectation of outcomes (“you should feel…”) 3. Social learning (reinforcements) 4. Genetic variants (biology)

v. Nocebo effect: negative expectations may increase level of anxiety experienced and may influence outcome of treatment. 1. Ex: warnings about side effects may lead to more side effects. vi. Placebos are used to evaluate effectiveness of new medications because they eliminate influence of expectation. The control group is blind to which of the substances is the inactive one. vii. Double-blind experiment: neither patient, nor observer knows which treatment the patient has received to ensure results of treatment are not influenced by prejudices of patient or observer. II.

Pharmacokinetic Factors Determining Drug Action a. Bioavailability: Amount of drug available in the blood to bind. Pharmacokinetics: part of drug action: the dynamic factors that contribute to bioavailability. i. Dynamic factors contributing to bioavailability of drug in the blood: 1. Routes of administration 2. Absorption and distribution 3. Binding 4. Inactivation 5. Excretion ii. Drug effect also depends on: 1. How rapidly the drug reaches its target 2. Frequency and history of prior drug use 3. Nonspecific factors characteristics of individuals and their environment b. Methods of drug administration influence the onset of drug action: (affect availability of drug to bind, alters rate of absorption – slow absorption provides opportunity for liver metabolism = less potent drug bc metabolized) i. Absorption: movement of drug from site of admin. to the blood. ii. First pass metabolism: potentially harmful chemicals pass and are chemically altered. Some therapeutic drugs take this path and must be given by injection or high doses. iii. Enteral methods: use the gastrointestinal tract; slow and dilute more. iv. Parenteral methods: bypass the GI tract includes injection, pulmonary. 1. Oral administration (PO): self-administered; slower but safest because it allows for a larger window to save those who overdose than those drugs that bypass the GI tract. Highly variable absorption and less-predictable blood levels.

2. Rectal administration: drug placed in capsule and inserted into rectum; used for those who are unable to take medication orally. May bypass first-pass metabolism depending on placement: a. Lower rectum: bypasses the liver b. Deeper placement: goes into liver 3. Intravenous (IV): most rapid, injected so that it goes directly into the bloodstream and does not get metabolized. Has the smallest window to save someone who overdoses (if any at all), and drug cannot be removed from the stomach like orally administered drugs. a. Drug abuse: IV injection allows for drug to reach brain instantly. Problems include uncertain doses, unsterile/shared needles (HIV). b. Usually impurities in the drug can block and get stuck in small vessels of the blood. 4. Intramuscular (IM): slower; injected into a muscle. Absorbs evenly over a period (1030 min, depending on blood flow), and can be slowed down with blood-constricting drug or vegetable oil (birth control). Can cause irritation. 5. Intraperitoneal (IP): rare in humans, but common in lab rats. Drug injected through abdominal wall into space surrounding abdominal organs. (faster than PO) 6. Subcutaneous (SC): injection just below the skin. Slow absorption but can be slowed down (prolonged) with vegetable oil or delivery device. Can vary due to blood flow. 7. Inhalation: drug absorbed by lungs. Rapid absorption because lungs have many capillaries. Drug effect is rapid. Impurities can get stuck in small blood vessels. 8. Topical: drug is applied to mucous membranes. Local effects mostly but can be absorbed into bloodstream. 9. Sublingual administration: drug placed under the tongue avoiding GI tract, enzymes, and first-pass metabolism (tablets that dissolve). 10. Intranasal administration: can cause local effects like relieve nasal congestion. But can also have systemic effects. Avoids first-pass metabolism, bypasses blood-brain barrier allowing high concentrations. Drug effect peaks in 15-30 min. a. Intranasal oxytocin being tested to treat Autism. b. Cocaine: is a vasoconstrictor and makes holes in the nasal septum; impurities in the drug cause inflammation of nasal tissues.

11. Transdermal: through the skin, administered with skin patches; controlled and sustained delivery of drug. Can avoid first-pass metabolism. 12. Epidural: injection delivered directly to the cerebrospinal fluid. Very rapid effect on the central nervous system, but not reversible. 13. Intracranial: Microinjection of drug to brain areas. 14. Intracerebroventricular: Microinjection of drug to ventricles in brain. 15. Infusion pump: implanted under the skin of the scalp programmed to deliver a constant dose of drug into cerebral ventricles. a. Used to treat brain infection, does not cross the blood-brain barrier. 16. Gene therapy: application of DNA that encodes a specific protein. a. Can be used to increase or block expression of a gene. b. Problems: immune reaction, viral vector may recover its ability to cause disease once placed in human cell & inserting the vector in the wrong place might cause tumors. c. Multiple factors modify drug absorption: once administered, a drug is absorbed into the blood to go to the brain (the main target for psychoactive drugs) i. Most important factor in determining plasma drug levels is the rate of passage through cell membranes. ii. Cell membranes are mostly phospholipids (water soluble) which have a negatively charged region (hydrophilic) and two uncharged tails (hydrophobic). 1. Proteins are inserted into the phospholipid bilayer and serve as receptors or channels; most molecules cannot pass unless fat-soluble. 2. Lipid-soluble drugs can pass through cell membranes by passive diffusion. 3. The larger the concentration gradient, the faster the diffusion. iii. Lipid solubility increases drug absorption and determines how readily it will enter the brain. 1. Heroin is more lipid-soluble than morphine, so it has more potency. 2. Heroin is a prodrug (dependent on metabolism) and metabolizes into morphine, or else it has no effect. iv. Most drugs are not lipid-soluble because they are weak acids or bases that ionize in water (completely breakdown in water). 1. Extent of ionization depends on pH level of the solution it is placed in. 2. Different fluids in body cause different drug ionization.

3. Stomach (very acidic 1.0-3.0), intestine (less acidic 5.0-6.6), blood (more basic 7.357.45). 4. pKa is the pH at which a drug would be 50% ionized and 50% non-ionized. a. Drugs that are weak acids ionize more in an alkaline environment. b. Drugs that are weak acids ionize less in an acidic environment. c. Drugs that are weak bases ionize more in an acidic environment. d. Drugs that are weak bases ionize less in an alkaline environment. 5. Highly-charged drugs are very poorly absorbed by the GI tract, cannot be administrated orally, and cannot cross the membrane. 6. Easily cross membrane if non-ionized (less charged). v. Aspirin (a weak acid) is more likely to remain in a non-ionized form in the stomach but it is fat soluble, so it will get across the membrane; due to concentration gradient it moves to the blood. Now it is more likely to be ionized (well dissolved) because it is in an alkaline environment. Aspirin also crosses easily into the intestines because it is fat soluble, and it will most likely ionize a little more there than the stomach because it is less acidic. It is not very readily available to cross into the blood because it doesn’t want to leave. vi. Other factors affecting absorption: 1. Rate stomach empties: small intestine has more surface area and slower movement of material = more absorption. Size and sex of individual: a larger person has more body fluid to dilute the drug. 2. Highest concentration of drug will occur where blood flow is greatest. 3. Drug redistribution: Drug concentration in organs w/a lot of blood will move back into the plasma to maintain equilibrium (can terminate drug action).

Chapter 3: Chemical Signaling by Neurotransmitters and Hormones I.

Chemical Signaling between Nerve Cells a. Synapse is the point of communication between neurons. i. Axodendritic synapse: a presynaptic axon terminal communicates with a postsynaptic dendritic spine. ii. Axosomatic synapse: a presynaptic axon terminal communicates with a postsynaptic cell body. iii. Axoaxonic synapse: a presynaptic axon terminal communicates with a postsynaptic axon terminal (to mediate neurotransmitter release). 1. If it reduced neurotransmitter release: presynaptic inhibition. 2. If it enhances neurotransmitter release: presynaptic facilitation. b. Transmission occurs only one-way (presynaptic cell to postsynaptic cell). i. Electron microscopy used to identify cell structure. ii. Synapse is surrounded by processes from astrocytes (they support the synapse and make sure the action potential maintains strength) iii. Synaptic vesicle: sac filled with neurotransmitters. iv. Mitochondria in the axon provide ATP (energy) for ion pumping and transmitter release. v. The receiving cell can be another neuron, a muscle cell, hormone releasing cell, or another type of releasing cell. 1. Neuromuscular junction: synapse between a neuron + muscle cell. c. Gap between neurons, or the synaptic cleft, is about 20 nm. i. Postsynaptic density: the fuzziness on the postsynaptic membrane filled with neurotransmitter receptors.

II.

Neurotransmitter Synthesis, Release, and Inactivation a. More than 100 neurotransmitters identified. b. Classical neurotransmitters: i. Amino Acids: Glutamate, GABA, Glycine. ii. Monoamines: Dopamine, Norepinephrine, Serotonin, Histamine. iii. Acetylcholine purines: Adenosine, Adenosine triphosphate (ATP). c. Non-classical neurotransmitters i. Neuropeptides: Endorphins + Enkephalins, Corticotropin-releasing factor. (CRF), Orexin/Hypocretin, Brain-derived neurotrophic factor (BDNF).

ii. Lipids: Anandamide, 2-Arachidonoylglycerol. iii. Gases: Nitric oxide (NO), Carbon Monoxide (CO), Hydrogen Sulfide (H2S). d. Criteria to classify a chemical as a neurotransmitter: (not all need to be met) i. Presynaptic cell contains chemical and mechanism to make it. ii. Mechanism for deactivating chemical is also present. iii. Chemical is released in the axon terminal when neuron is stimulated. iv. Receptors for chemical are present on postsynaptic cell. v. Direct application of chemical or agonist has the same effect on postsynaptic cell as stimulating the presynaptic neuron. vi. Applying an antagonist that blocks the receptors inhibits both the chemical’s action and the effect of stimulating the postsynaptic neuron. e. 1 neuron can make one to several neurotransmitters. i. Vesicles can hold one or both transmitters. 1. Small vesicles: hold classical neurotransmitters made near the axon terminals. Enzymes to synthesize these are transferred to the axon terminals. 2. Large vesicles: hold non-classical neurotransmitters (neuropeptides) made in the cell body. Precursor proteins are transferred to the axon terminals alongside a classical neurotransmitter. Takes longer to replenish (remake). f. Neuromodulators: can enhance, reduce, or prolong the action a neurotransmitter. i. May diffuse away from the site to influence other cells (volume transmission – anywhere that has a receptor), in contrast to synaptic transmission (wiring transmission). g. When a wave of depolarization reaches axon terminals, voltage gated Ca2+ channels open and Calcium ions rush into cell. i. High Calcium levels trigger neurotransmitter release through vesicles “docking” with membrane. Many proteins involved in this process. ii. Calcium channels are concentrated in active zones of the terminal membrane. h. Exocytosis: Ca2+ binds to receptors and results in fusion of vesicle membranes with the cell membrane, releasing the neurotransmitter into the cleft. i.

Vesicle recycling: during exocytosis vesicle membranes are added to the membrane (or they become part of the membrane). i. The vesicle membrane is recycled by endocytosis; portion is pinched off and fused with an endosome to refill. ii. Many proteins are involved in exocytosis and vesicle recycling:

1. Synaptobrevin: helps vesicle fuse to terminal membrane. (Most abundant protein found in vesicles) 2. Botulism: toxin that blocks neurotransmitter release at neuromuscular junction. iii. Vesicle recycling must occur, or membrane will continue getting thicker. j.

Three proposed models for vesicle recycling: i. Clathrin-mediated endocytosis: 1. Vesicle fuses to membrane and releases neurotransmitter. 2. Vesicle flattens into membrane. 3. Distant from release site (15-20 sec), it begins getting recycled. 4. Clathrin coats the membrane to signal it to detach and create the vesicle again. 5. Takes time. ii. Ultrafast endocytosis 1. Vesicle fuses to membrane and releases neurotransmitter. 2. Vesicle DOES NOT flatten into membrane. 3. Close to release site (1-2 sec), vesicle comes back up. 4. Vesicle finds endosome, attaches to it, then new vesicles detach from the endosome using a Clathrin coat that signals the endosome to detach and create vesicle again. 5. Occurs very quickly. iii. Kiss and run 1. Vesicle fuses to membrane VERY BRIEFLY, and releases neurotransmitter. 2. Same vesicle remains empty for a brief period and quickly refills.

k. Bulk endocytosis: occurs when neurons are stimulated very strongly. i. Takes place distant from the release site of the neurotransmitters. ii. Uses endosomes and Clathrin to bind new vesicles off the endosomes. l.

Recycling mechanisms only occur with small vesicles (containing classical neurotransmitters, locallymade ones). i. Neuropeptide recycling does NOT occur in the terminals because precursor proteins are packaged in the cell body.

m. Lipid and gaseous transmitters readily pass through membranes and can’t be stored in vesicles. i. They are made on the spot and leave the cell once their job is done. ii. They are retrograde messengers: released by the postsynaptic cell to travel back up to the presynaptic cell, after a traditional synapse. n. Neurotransmitter release is regulated by:

i. Rate of neuron firing. ii. Probability that vesicles will undergo exocytosis (10-90% chance, may need more action potentials so this is not set in stone). iii. Auto receptors: Respond to same neurotransmitters to regulate release. 1. Terminal auto receptors: activated by the same neurotransmitter, inhibits further release. 2. Somatodendritic auto receptors: Slow down rate of neuron firing, reducing rate of neurotransmitter release indirectly. 3. Some drugs block or stimulate auto receptors. a. Block auto receptor = too much in cleft b. Stimulate auto receptor = too little in cleft c. A drug for Parkinson’s disease symptoms (Apomorphine) activates Dopamine auto receptors = less dopamine release = less locomotor movement. iv. Heteroreceptors: receptors that respond to different neurotransmitters released at axoaxonal synapses. 1. Can reduce or enhance amount of transmitter being released. o. Inactivation of neurotransmitters: to stop signal transmission, must be removed from cleft. i. Broken down by enzymes. ii. Reuptake into the cell that released them. 1. Transporters are NOT auto receptors. a. Transporters are a mechanism of inactivation of the neurotransmitter by taking it back up into the cell. b. Auto receptors are a mechanism of regulation of the neurotransmitter by halting neurotransmitter release into the cleft. 2. Some psychoactive drugs block transporters, so more neurotransmitter is in the cleft meaning more binding is occurring meaning enhanced transmission. a. Cocaine blocks dopamine transporters meaning more dopamine stays in the cleft making people feel good. III.

Neurotransmitter Receptors and Second Messenger Systems a. Neurotransmitter receptors are proteins on the cell membrane. i. Transmitters bind to the receptors and activate either an inhibited or excitatory response on the postsynaptic cell.

ii. One neurotransmitter can have different effects on the postsynaptic cell depending on what receptor it binds to. 1. They can bind to more than 1 receptor subtype. 2. Drugs can be designed to affect specific subtypes of receptors, resulting in less side effects. But it is difficult. iii. They do not act like transporters because transmitters do not go through them, rather only bind to it and pass a signal, then detach. b. Two types of transmitter receptors: i. Ionotropic receptors: 4 or 5 subunits with an ion channel in the middle. When activated, it opens and allows ion flow through their ligand-gated ion channels. 1. When a channel is desensitized, it remains closed even though ligand is bounded to receptor. This can occur with drug use. 2. Some receptors are Na+ channels = depolarization (EPSP) 3. Some receptors are CL- channels = hyperpolarization (IPSP) 4. Others allow flow of Na+ and Ca2+, Ca2+ can act as a second messenger and have effects other places in the cell. ii. Metabotropic receptors: 1 subunit w/7 transmembrane domains, activate G proteins, they act slower but have long lasting effects. 1. They do not contain ion channels within them. 2. Most medicines use these receptors. 3. Ligand activates metabotropic receptor activating a G-protein: a. Can inhibit or activate ion channels (Can trigger K+ channels to open, and K+ moves out of the cell). b. Can stimulate or inhibit effector enzymes in the cell membrane that synthesize second messengers. 4. The neurotransmitter is the first messenger, and the second messenger is a molecule inside the cell that carries out the biochemical change signaled by the first messenger. c. Many receptors have additional binding sites called allosteric sites. i. Allosteric modulators: molecules (such as drugs) that bind to allosteric sites and alter the functioning of the receptor. 1. They can have a positive or negative effect on receptor signaling. 2. Neurotransmitters bind to non-traditional receptors. 3. They only modify the effects of an agonist, they have no effect when binding alone.

4. They often have greater receptor subtype selectivity than agonists and antagonists. a. Modulators of metabotropic receptors may result in better drugs to treat psychiatric and neurological disorders. ii. Allosteric modulation of...