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psych 119 mt1(self)
| Question | Answer |
|---|---|
| What are the two major divisions of the nervous system? | Central NS and Peripheral NS |
| What are the two major divisions of the PNS? | Somatic and Autonomic NS |
| What are the two divisions of the ANS? | Sympathetic and Parasympathetic NS |
| What are the two parts of the CNS? | Brain and Spinal Cord |
| What are the two kinds of cells in the brain (CNS)? | Neurons and Glial cells |
| In which NS do drugs primarily act and where are the side effects? | Primarily in CNS w/ PNS for side effects |
| What does the Cerebellum do? | sensorimotor coordination / movement; stability / posture *effected by alcohol |
| What does the Brain Stem do? How is it organized? | Control basic functions / reflexes organized in clusters of neurons (produce NTs) |
| What are the parts of the Brain Stem? | Pons, Medulla, Midbrain |
| Describe the Pons | Raphe nuclei (creates serotonin) and Locus Coeruleus (produces Norepinephrine) |
| Describe the Midbrain | Substantia Nigra / Ventral Tegmental Area (produces DOPAMINE) * movement, reward |
| What are parts of the Forebrain? | Cerebral Cortexx, Limbic System, Basal Ganglia, Diencephalon |
| What are the parts of the Diencephalon? | Thalamus (receives all sensory/ motor input) Hypothalamus (Internal environmental, Drives, Pituitary gland) |
| Describe the Basal Ganglia | Globus pallidus, striatum (putamen, caudate, dorsal vs. ventral (motion vs reward)) targets of dopamine (VTA, SN) |
| What are the parts of the Limbic System | Amygdala (emotion/mood, fear, etc; effects by beta-blockers, alcohol) Hippocampus (Long term / spatial memory) (THC) |
| Describe the Cerebral Cortex | cortex = shell two hemispheres 4 lobes (frontal, parietal, temporal, occipital) |
| What does the frontal lobe do? | higher cognition: language, control, working memory, decision making |
| What are the direction in the brain? | Anterior (front), Posterior (back), Superior (above), Interior (below) Lateral (Outside), Medial (middle) |
| Directions in the longitudinal axis | up --> dorsal down --> ventral |
| What are neurons? | nerve cells, basis for all brain function **Specialized for communication, generate & propagate electrical / chemical signals (internal, electric; external -> chemical) *Where drugs act |
| what are glia (glial cells) | support cells two types in CNS --> Astrocytes (BBB), Oligodendrocytes (Myelin --> speed up neuronal communication) |
| What are the neuron parts and what do they do? | Cell Body (som) [cytoplasm + organielles, nucleus) Dendrites (recieve info) Axon Hillock (btwn cell body and alon) axon (terminal with NTs, sends info) |
| What is convergence vs divergence? | convergence = each neuron receives input from many other neurons divergence = each neuron sends output to many neurons |
| What does more dendrites mean / more dendritic spines | more input |
| What are axons | wrapped in glial cells (myeline sheath --> oligodendrocytes) have vesicles with neurotransmitter molecules which are sent to other neurons |
| What is a Synapse | the meeting of 2 neurons (presynaptic cell and postsynaptic cell) WHERE DRUGS ACT |
| What are the 3 types of synapses? | Axodendritic (pre-axon to post-dendrite) Axosomatic (pre-axon to post-cell body) Axoaxonic (pre-axon to post-axon (which can have the other synapse to another neuron) |
| What is the difference between Gray and White Matter | Gray matter - neuron bodies and dendrites White matter = axons (organized into tracts, or in the PNS, nerves), glial celsl |
| What are the two types of glial cells | Astrocytes, oligodendrocytes |
| Which brain structure is implicated in loss of balance during alcohol intoxication? | Cerebellum |
| What is a neuron's membrane? | Neuron's skin, a fatty (lipid) bi-layer on both sides are ions --> membrane stops ions from passing freely in/out of neuron keeps ions at disequilibrium |
| What are the ions that interact with the neuronal membrane? | Potassium, Sodium Calcium, Chloride Proteins |
| What is the resting membrane potential | the difference between the inside of the neuron to the outside = -40 mV to -90 mV (-65/70 mV difference) *neuron is polarized |
| What are the 2 electrochemical forces that maintain balance? | Concentration Gradient (stronger), Electrostatic Pressure |
| What is the concentration gradient | nature likes concentration to be equal across boundaries --> ions want to move from high concentration to low (DOWN the concentration gradient --> towards equilibrium) |
| What are the Ion amounts inside and outside the membrane (high vs low)? | Higher concentrations OUTSIDE: sodium, chloride, Calcium Higher concentration INSIDE: potassium, protein |
| What is electrostatic pressure | positive likes to go to negative |
| What are the neuronal forces? | ion channels, the pump (both live in the membrane) |
| What are Ion channels ( = Gates) | gates for specific ions when closed, don't allow ion flow when open, allow ion flow |
| what are the 3 types of ion channels? | 1. resting channels (open at rest, K+) 2. voltage-dependent/gated (open only at certain voltage) 3. ligand dependent (aka receptors, like a lock, need a key) |
| How does the membrane look at rest? | resting potential -65/70 mV more K+ on the inside More Na+/Cl- outside Na+/Cl- channels closed at rest resting K+ channels open (some K can flow in both direction but more flows out ** CG stronger than EP) |
| What is the Sodium-Potassium Pump (NA+/K+) | It's a transporter Lets 2 K+ ions in and kicks 3 Na+ ions out Gets paid with ATP |
| What disturbs the neuron's rest? | input from other neurons = neurotransmission |
| What can inputs (NTs) do? | Opens ligand-gated ion channels ions flow down concentration gradient |
| If a Na+ channel opens, what happens? | Na+ flows inside |
| What do the different inputs (ie what channel opens) do? | Opens K+ / Cl- --> K+ goes out, Cl- goes in --> membrane becomes more negative (hyperpolarized) --> Inhibitory Post Synaptic Potential (IPSP) Opens Na+ / Ca 2+ --> Na+ and Ca 2+ goes in --> membrane becomes more positive (depolarized) --> EPSP |
| What happens when inputs co-occur? | convergence (Summation) |
| How does the neuron go from EPSP to Action Potential | if summation/integration at the axon hillock reaches -50 mV --> AP |
| What is the action potential? | neuronal firing, an all-or-nothing change in the membrane potential++ |
| what are the steps leading up to action potential? | 1.K+ channels open at the resting potential 2.local EPSPs depolarize the neuron to threshold 2-3.integration/summation of potentials depolarizes axon hillock enough to open VG Na+ channels 3.VG Na+ channels open & depolarize the neuron rapidly to peak |
| What happens once the Neuron reaches AP? | 3-4. Action potential reaches peak (+40 mV) 4. Na+ channels close (refractory). VG K+ channels open (K+ out), repolarizing the neuron 5. all gated channels close, neuron is repolarized, membrane returns to resting potential |
| How does the AP act in the neuron? | propagates/regenerates (at nodes of ranvier) down the axon to the terminal faster in myelinated axons AP reaches the axon terminal via saltatory conduction |
| What is saltatory conduction? | saltatory = in leaps once threshold is reached at hillock, VG Na+ channels open initiating AP Na+ spreads rapidly to the next node - rapidly depolarizing it to threshold - opening Na+ channels, triggering the AP And so on... |
| Describe the steps leading to Neurotransmission | 1.AP reaches terminal(Na+) 2.depolarizes membrane potential (Ca2+ open) 3.Ca2+ causes synaptic vesicles fuse with membrane (exocytosis) 4.NTs released 5.NTs diffuse across the synaptic cleft 6.NTs bind to postsyn receptors 7.IPSP/EPSP on post neuron |
| what are the phases of a neuron (before, during, and after AP)? | resting, threshold, rise, peak, refractory, resting |
| What are neurotransmitters? | chemicals used for signaling synthesized by neurons (soma/synapse) central to drug action |
| What are the 2 main structural classes? | 1. "Classic" small molecules - acetylcholine, amino acids, purines, monoamines 2. "non classic" NTs - neuropeptides, lipids, gases |
| How many NTs can be synthesized / released by the neuron? | MULTIPLPE typically a classic and non-classic --> small & big vesicles (sometimes two per vesicles) |
| What are the 3 NT functional classes? | 1. (Primarily) Excitatory 2. (Primarily) Inhibitory 3. Neuromodulators |
| How do the functional classes relate to AP? | Excitatory NT --> EPSP --> AP more likely Inhibitory NT --> IPSP --> AP less likely |
| Are structural and functional classes independent or dependent? | independent (NT action depends on receptor behavior) |
| How do receptors and NTs Interact? | key and lock! a single key can fit in several locks (not open) or fit & open several locks |
| What are receptors? | Proteins that live in the membrane (ie. ion channels, pumps) have a specific "shape" NTs bind to the receptors are named after the NTs multiple receptors per NT |
| what are the two main types of receptors | ionotropic, metabotropic |
| What are ionotropic receptors | ligand -gated ion channels! Have 4-5 subunits --> together form an ion channel closed until NT binds, which opens ion channel rapidly Ca2+ as 2nd messengers |
| What are Metabotropic Receptors? | No Ion Channel/subunits have lock spots linked to G-Protein inside --> indirectly open ion channels (effects depend on channel) alter other cell activities slower & longer-lasting |
| What is an agonist? | mimic the action of the NT |
| What is an antagonist? | sometimes blocks receptors |
| Where are receptors? | Autoreceptors, on postsynaptic cell |
| What are Autoreceptors? | On presynaptic neuron, for the NT produced by it; negative feedback, reduce own synthesis/release? |
| What are the 2 types of glial cells? | Astrocytes, Oligodendrocytes |
| What are the 3 main mechanisms of NT Elimination? | Reuptake, Enzymatic degradation, glial uptake (Not mutually exclusive) |
| Describe Reuptake | taken back up typically into pre-synaptic cell NOT AUTORECEPTORS Just move NTs into cell --> repackaged, enzymatic degradation |
| What is the outcome of SSRIs? | Inhibit the reuptake of serotonin --> increases extracellular serotonin |
| Describe Enzymatic Degradation | NT meets enzymes --> leads to chemical breakdown of NT --> create inactive metabolites / byproducts (if presynaptic --> metabolites may be resynthesized into NTs and repacked) |
| Describe Glial Uptake | Transporters, NT --> nearby astrocytes, broken down |
| Can NT Elimination be altered by drugs? | YES |
| What is Glutamate and its effects? | Major excitatory neurotransmitter Amino Acid NT (used in other cell functions, present everywhere) Increase Glu --> stimulation decrease/block Glu --> sedation involved in -- everything (synaptic plasticity, LTP, addiction) |
| What are Glutamate affecting Drugs? | Alcohol, PCP, Ketamine, etc |
| Describe the types of Glutamate Receptors? | Ionotropic (3), metabotropic (8) Ionotropic - EPSP, (Glu binding, influex of Na+, depolarization) AMPA, Kinate, NMDA (named after other compounds that selectively bind to them & agonize them) |
| What are the 3 main Ionotropic Glutamate receptors? | AMPA, NMDA, Kinate |
| Describe the NMDA receptor (binding conditions and effects)? | requires Glu binding requires co-agonist (Glycine/D-Serine) requires depolarization ("Coincidence detector") --> Release Mg+ block (Synaptic plasticity & LTP) when open: allows Na+ & Ca2+ (2nd messenger) **Ligand-gated & voltage gated ion channel |
| What drugs act on the NMDA Glu receptor? | PCP , Ketamine |
| What is Glutamate's function? | Excitatory, might enhance cognition / learning DOOGIE MICE |
| What are the Doogie Mouse Experiments? | Doogie mice were genetically engineered to overexpress NMDA receptor subunits (more efficient) 1. they showed mice objects A&B 2. after delay, showed A&C 3. measure looking like (longer time --> new = bad memory) |
| what were the results of the Doogie mouse experiments? | Doogie mice have better memory pain sensitive --> too much Glu is toxic |
| What is the Glutamate Elimination Mechanism? | Combination of reuptake into glutamate producing neurons AND ESPECIALLY uptake by astrocytes (glial cells), enzymatic degradation |
| Fill in the blank: charge inside the neuron is always more _____ relative to ______ | negative, outside the cell |
| Which division of the NS is responsible for transmitting pain information from the hand to the brain? | PNS |
| Describe Glu Elimination | 1. Neuron reuptakes glutamate (EAAT3 transporter) 2. repackages it OR 1. Astro uptakes glutamate 2. glutamate --> glutamine 3. transports glutamine out 4. neuron takes it 5. turns it into glutamate 6. neuron repackages glutamate |
| Describe GABA | Amino Acid NT Inhibitory synthesized from glutamate most receptors in: cerebral cortex, hippocampus, substantia nigra increase GABA --> sedative, hypnotic block GABA --> leads to seizures, convulsions |
| What are some GABA agonists? | Alcohol; Valium, Ativan, Klonopin; Anesthetics |
| What are the GABA Receptors types / effects? | 1 Ionotropic -> GABA A 1 metabotropic -> GABA B |
| Drug effects on GABA A receptors? | Drugs can bind to GABA A Receptor sub units, most don't activate --> modulate Enhance GABA @ GABA A --> increase inhibit |
| Describe GABA A effects | - when GABA binds --> CL- allowed in --> hyperpolarization FAST different subunits on receptor complex - 5 units per receptor, 4 types of subunits, 3-6 subtypes EACH Subunit have several locks |
| Describe GABA B effects | ultimately opens K+ channels, lets K+ out --> hyperpolarization inhibits second messenger formation slowwwwwwww |
| What is the GABA Elimination Mechanism? | Reuptake by GABA neurons Uptake by astrocytes (glial uptake) enzymatic degradation |
| Describe Monoamines | NTS made of a single amine group - Norepinephrine (noradrenaline) -Dopamine -Serotonin (5-HT) -(histamine) -Catecholamines (DA & NE/E) -Indolamine (5-HT) - Classic Monoamines: Catecholamines + indolamine - MODULATORY |
| Which NT is common to Parkinson’s disease, Ritalin, chocolate cake, Schizophrenia, and some antidepressants? | Dopamine |
| What Drugs is Dopamine affected by? | Cocaine, amphetamines, and meds (depression, schizophrenia, ADHD) secondarily affected by all abused drugs |
| How is Dopamine synthesized? | dietary tyrosine (--> L-DOPA-->DA) |
| Where is dopamine produced? | MAINLY in midbrain : Substantia Nigra (SN), Ventral Tegmental Area (VTA) |
| What are the dopamine Pathways? | Mesocorticolimbic Pathway - VTA -> limbic system (NAcc) & cerebral cortex (PFC) - reward, motivation, executive control, emotion Nigrostriatal Pathway - Substantia nigra -> dorsal striatum - voluntary movement (ie parkinsons) |
| What are the functions of Dopamine? | voluntary movement codes for rewards, salience, novelty role in learning |
| What is a reward? | something motivating |
| What are the types of rewards? | natural/primary reward --> something that the brain (intrinsically) interprets as positive/motivating Secondary Rewards --> something that you learned to interpret as positive/motivating |
| Reinforcing definition | increase likelihood of repeating paired behavior |
| How is Dopamine related to rewards? | 1. Dopamine neurons fire in response to (unexpected) rewarding stimuli 2. Dopamine neurons fire in response to novel/intense stimuli |
| What happens to dopamine when the reward is better than expected? | dopamine neurons fire to EXTRA reward |
| What is a reward is missing, what happens to DA? | DA firing is REDUCED |
| What is DA: Reward Prediction-Error Signal? | signals difference between what was expected and what was received |
| What are the DA Receptors and how are they organized? | 5 subtypes two families D1 (D1 & D5), and D2 (D2, D3, D4) Some auto-receptors all metabotropic |
| Where are the D1 / D2 Receptors? | Striatum, ventral striatum / nucleus accumbens |
| What does the D1 Receptor do? | G protein G s --> stimulate adenylyl cyclase --> stimulates second messenger synthesis (cAMP) --> indirectly depolarizes membrane potential |
| What does the D2 receptor do? | G protein G i --> inhibits Adenylyl Cyclase --> inhibits cAMP synthesis --> indirectly hyperpolarizes (ALSO indirectly opens K+ channels) |
| What are the main mechanisms of DA Elimination? | 1. reuptake - DA transporter(DAT) --> repackages 2. enzymatic degradation (MAO-A&B and COMT) |
| Which NT is common to pasta, LSD, your intestines, some anxiety medications, and most antidepressants? | Seratonin! (AKA 5-HT) |
| What is the function of seratonin? | Mood, motor output |
| What is seratonin synthesized from? | dietary tryptophan (--> 5-HTP --> 5HT) |
| Where is 5-HT mostly located? | in the gut! or in CNS --> localized production |
| Describe the Seratonin Receptors | Over 14 types mostly metabotropic (don't directly open ion channels) Mixed/opposing effects --> neuromodulator some are auto-receptors (regulates output at synapse) |
| what is Seratonin receptor that is an exception? | 5-HT 3 (ionotropic & excitatory) |
| Describe 5-HT 1A | Common in amygdala, hippocampus, dorsal raphe (auto-receptor) Binding ultimately opens K+ channels (inhibitory) changes protein synthesis via 2nd messenger Agonism: reduces anxiety, eating, aggression |
| Describe 5-HT 2A receptor | common in cortex, striatum, accumbens binding ultimately opens Ca 2+ channels and changes protein synthesis (via 2nd messenger) Agonism: increases motion & hallucinations |
| What are the main mechanisms of Seratonin elimination? | Reuptake - 5HT transporter (SERT) Enzymatic degradation - MAO |
| Describe Norepinephrine (noradrenaline) | Catecholamine/monoamine - synthesized from DA - localized production : Locus Coeruleus - wide distribution |
| function of norepinephrine | adrenaline - wakefulness, arousal - cognition/memory -emotional memory |
| Which NT is common to Black Widow Venom, Alzheimer’s disease, Sarin Gas, Nicotine, Mandrake, Botox, and some psychedelic drugs? | Acetycholine (ACh) |
| What type of molecule is ACh? | Classic/small molecule NT |
| where is ACh located? | PNS (somatic and autonomic sections) |
| What is the functional type of ACh? | Modulator |
| What are the types ACh Receptors? | Muscarinic (Metabotropic) Nicotinic (Ionotropic) |
| Describe Muscarinic receptors | Metabotropic (GPCR)M1-5 --> different effects second messengers some ultimately open K+ channels |
| Describe Nicotinic Receptors | Ionotropic Fast opening of Na+ channel (& K+) - In CNS also Ca 2+ On axons --> exocytosis different subtypes |
| Degradation of AChE leads to more or less Ach binding? | MORE |
| What is the primary mechanism for ACh Elimination? | Enzymatic Degradation by AChE (degrades into choline which is reuptaken) |
| What is Pharmacokinetics? | The study of the factors that determine bioavailability (what you do to the drug) |
| What is pharmacodynamics? | the study of the mechanisms of action/drug effects = what the drug does to the brain and body |
| What is bioavailability? | how much of the drug actually reaches target |
| what is time course: | onset and duration of effects |
| What are the parts of pharmacokinetics? | Route of administration, absorption, distribution, metabolism, elimination (RADME) |
| What is the route of administration mean? | how we take a drug |
| what does absorption mean? | how the drug gets into the blood stream |
| what does distribution mean (in RADME)? | how it gets around the body |
| what does metabolism mean (in RADME)? | how drugs are broken down |
| what does elimination mean (in RADME)? | of drug or metabolic waste product |
| What are the different routes of administration? | 1. Oral administration (PO) 2. Inhalation 3. mucus membranes/skin Injection (IV; IP, IM, SC) |
| Describe Oral Administration | Relatively safe Slow and complicated/unpredictable (.5-3 hours) |
| What must a drug go through/ need to reach the brain through oral administrain? | -must dissolve in stomach fluid -survive stomach acid (cocaine/insulin..) -potential enzymatic degradation -delayed by food -must have lipid solubility (penetrate stomach lining) -pass into blood stream but first pass at liver ->might metabolize |
| Describe R2. Inhalation | Fastest and Direct (mere seconds) 1. lung area + bloodflow 2. lungs capillaries -> left heart -> brain Problems: drug type, irritation, dosing, rapid offset |
| Describe R3. Mucus Membranes/Skin | 1-30 min examples: skin, sublingual, snorting, vaginal, rectal membranes rich in blood supply --> bloodstream absorption Issues: dosing, local effects on membrane, some molecules absorb better than others |
| Describe R4 Injection | 10-30 seconds Most common is IV: - rapid, accurate dosing -> high doses -strong/fast effects (depending on location) - most dangerous for OD / bad reactions - blood vessels collapse -infections |
| What are the different types of Injection? | Subcutaneous (penetrates membrane), Intramuscular, Intravenous (most common), IP (in bone(?)) |
| What does absorption depend on? | route of administration, dose, dosage form (pill/powder/liquid), drug lipid solubility |
| how does drug lipid solubility work? | passive diffusion across lipid membranes; - more lipid soluble -> more rapid diffusion) DOWN the concentration gradient |
| How long dose it take for full circulation of the bloodstream? | 1 minute |
| How long does a drug take to distribute through the body? | few minutes (redistribute throughout body tissue) |
| T/F : most of the drug is in the brain? | false |
| What does the time course of a drug in the blood level depend on? | Routes of administration |
| What is Depot Binding? | Temporary inert binding sites in body that reduces concentration of drug in blood and delays onset/peak |
| when are drugs released from depot binding and what does it do? | released when drug concentration is lower/ other drugs compete - delay metabolism/elimination - cause drug interaction |
| What membranes is the rate of distribution affect by? | stomach lining, capillary walls, cell membranes, placental barrier, depot binding, brain distribution (blood brain barrier) |
| What is the blood brain barrier (BBB)? | Barrier between blood and brain protects brain from toxins |
| What is the differences between BBB and regular capillaries? | Regular capillaries - have porous walls, covered with glial sheath BBB - tight junctions (no porous walls), coverage by astrocyte glial cells |
| How do drugs pass through the BBB and what stops it? | Have to pass through capillary wall, glial sheath; "transmembrane diffusion" rate of passage determined by 1. size of drug molecule 2. lipid solubility -->drugs have to be small, lipid soluble, not "bad" |
| How are drugs metabolized? | undergo enzyme-catalyzed chemical changes / breakdown |
| First Phase of Metabolism? | 1. drug meets enzyme 2. enzyme breaks drug into metabolites (typically less lipid soluble and inactive) 3. typically in liver |
| What is the 2nd phase of metabolism? | other compounds binding to metabolites |
| what are active metabolites (and their drug)? | - Caffeine --> Theobromine - Codeine -> morphine |
| What are the enzymes in metabolism? | Cytochrome p450 family (CYP450) does most - CYP-3A does 50% of phase 1 metabolism |
| what are factors influencing metabolism? | 1. individual differences (ie. age) 2. genetic variation 3. drug/enzyme competition 4. enzyme inhibition - ie. MAOI (MAO, P450), SSRIs 5. enzymatic induction (only some drugs) 6.metabolic cross tolerance |
| How does MAOI work? | inhibits MAO --> tyramine not metabolized --> toxicity |
| How do SSRIs work metabolically? | inhibit CYP-2D6 --> Codeine not metabolized --> ineffective |
| What is tolerance? | diminished response to a drug after exposure to that drug often requires repeated exposure (but not always) |
| What are some examples of metabolic cross tolerance? | Alcohol and some anesthetics (2E1) cigarettes and caffeine, fluvoxamine/Duloxetine (1A2) rifampin and benzos, Many SSRIs/SNRIs (3A4) |
| What is the grapefruit effect? | GI enzymes break down drugs (CYP 3A4) bergamottin in grapefruit inactivates enzymes! for some drugs: results in less metabolism --> more drug absorbed --> elevated levels which drugs? those metabolized by CYP-3A4 (fentanyl, benzos, etc) |
| Where are most drugs are metabolized? | the liver (can lead to liver damage) |
| What is half life? | the amount of time required for removal of 50% of the drug from the blood stream |
| what are traits of half life? | -exponential -constant rate (Not amount) -measured from the moment of peak plasma concentration is reached -can take a long time -longer in some people |
| what does half life depend on? how long it takes? | depends on drug (time varies widely between drugs, individual differences, enzyme availability, depot binding) minute to days |
| The same amount of drug is metabolized with every half life | False (The same %, but a different absolute amount is metabolized with every half life) |
| what are drug effects? | alterations in physiological or psychological function that result from drugs |
| what are specific drug effects? | resulting from biochemical interaction with tissue |
| what are the categories in specific drug effects? | acute vs chronic primary vs secondary therapeutic/intended effects vs side effects |
| what are non-specific drug effects? | effects that are not due to the drug itself based on individual differences (mood, attitudes, expectation) -> psychologically dependent |
| what is the placebo effect | when a pharmacologically inert compound (sugar pill) leads to physiological/psychological changes |
| what is a double blind experiment? | two groups, identity unknown to anyone |
| what is an example of a non-specific drug effect? | placebo effect |
| How can we measure a specific drug effect while the placebo effect exists? | Double blind experiment with drug vs placebo compare relative difference treatment - placebo = specific drug effect |
| How is drug action defined? | the molecular changes produced by the drug when it binds - specific, acute, primary effect - mechanism of action |
| what is "mechanisms of drug action"? | how drugs work (psychoactive drugs interfere with brain function - synaptic transmission) - drugs modulate NT systems that are already there: no unique effects --> increase/decrease effects of NT system |
| what are the 11 drug mechanisms of action (that don't have counterparts)? | 1. drug serves as NT precursor (+) 2. drug inhibits synthesis (-) 3. drug prevents storage in vesicles (-) 10. drug inhibits NT degradation (+) 11. drug blocks reuptake (+) |
| what are the 11 drug mechanisms of action (with counterparts)? | 4/5. drug stimulates(+)/inhibits(-) release of NT 6/7. drug stimulate(+)/blocks(-) postsynaptic receptors 8. drug stimulates autoreceptors; inhibits release of NT (-) 9. drug blocks autoreceptors; increases realse of NT (+) |
| Give examples for each of the 11 drug mechanisms? (1-6) | 1. L-DOPA(DA) 2. Tryptophan->5HTP->5HT, hydroxylase, Inhibitors(5HT) 3. Reserpine(DA,NE), Vesamicol (ACh) 4. Amphetamines, Methamphetamines (DA); MDMA(5HT) 5.BOTOX(locally) 6. Nicotine, THC, alcohol, Heroin |
| Give examples for each of the 11 drug mechanisms? (7-11) | 7. Caffeine, Schiz meds 8. Clonidine (NE) 9. Yohimbine (NE) 10. MAOIs (DA, NE, 5HT); Sarine Gas (ACh, PNS) 11. Cocaine & ritalin (DA); SSRIs & Tricyclics (5HT) |
| Characterizing Drug Action? | Drugs modulate NT systems that are already there act on NT availability/release act at receptors action is relative to baseline NT action |
| Describe Agonists | 1. relative to NT --> increases NT action (DA, ACh agonists) 2. relative to receptor -> binds, activates like NT/increases the effect of NT (ACh, 5HT) selective vs non, competitive vs non, full vs partial |
| Describe Antagonists | 1. relative to NT -> decreases NT action(functional definition) 2. relative to a receptor -> binds and blocks / decreases the effect at a receptor (DA, Glu) selective vs non, competitive vs non |
| What NTs are eliminated through reuptake? | Glutamate, GABA, Dopamine (w/ DAT), 5-HT (w/ SERT), Norepinephrine |
| What NTs are eliminated through Enzymatic Degradbation? | Glutamate, GABA, Dopamine (by MAO, COMT), 5-HT(MAO), Norepinephrine, Acetylcholine (AChE) |
| What NTs are eliminated through Glial Uptake? | Glutamate, GABA |
| What happens to drugs that are too lipid-soluble to be excreted naturally through urine? | They are metabolized (enzyme breakdown -> drug metabolites) |
| What was Levine 1973? | Classic ulcer experiments to test placebo effect |
| What does it mean for a Drug to be selective? | it is specific to a single receptor (type) ie. nicotine only binds at nicotinic receptors, not muscarinic; - ketamine binds at NMDA but not Kainate /AMPA/other Glu receptors |
| What is affinity? | binding strength of a ligand to the receptor (how tight of a fit of a ligand to a receptor) |
| what does competitive/Non-competitive drug classification mean? | refers to location on recetpr competitive = same as NT non-competitive = not the same as NT ex. Nicotine binds in same location as ACh; ketamine binds to a DIFFERENT location than glutamate |
| What happens if drugs and NTs/more drugs want to bind to the same spot at the same time (competitive)? | the one with the higher affinity stays displacement can occur (sometimes w NTs too) |
| What is efficacy? | thee ability to activate the receptor (initiate change/action at that receptor) |
| What are the different efficacys of drug types (agonists, antagonists, NTs) | NTs have a high efficacy (sometimes max) antagonists = 0 efficacy ex. ketamine = moderate affinity but 0 efficacy at NMDA for agonists, efficacy varies |
| what does full vs partial measurement / classification refer to? | ONLY for agonists refers to the degree of receptor activation a measure of efficacy of activating the receptor |
| what is the difference btwn full vs partial agonists? | full : fully activates receptor = maximum biological response = max efficacy partial = only partly effective/ activating |
| What are NTs at their own receptors (drug characterization)? | agonists, full (max/high efficacy), non-selective (moderate to high affinity to all their receptors) |
| What is Glutamate drug characterization at glu receptors? | full non-selective endogenous agonist |
| What is Nicotine's drug characterization? | selective, competitive nAChR agonist |
| What is Ketamine's drug characterization? | selective, non-competitive NMDA antagonist |
| What happens when we stimulate the MCL DA (Mesocorticolimbic Dopamine) system in rats? | Releases DA makes rats want to do it again MCL stimulation --> DA = reinforcing |
| What was DiChiara & Imperato 1988 investigating? | If MCL DA is common to all addictive drugs |
| How did DiChiara & Imperato 1988 test their hypothesis? | Administer "addictive" vs "non-addictive" drugs measured DA/metabolites in two different locations (using dialysis) - if no different, different regions shouldn't show inccrease DA |
| In DiChiara & Imperato 1988, what was the results in the VS and DS? | VS had increased DA (spiked up), but DS had no increase (even negative DA firing) |
| All addictive drugs have what in common as a common secondary effect (found by DiChiara & Imperato 1988)? | They all have MCL DA |
| What is the difference between the primary and secondary specific effects of drugs? | primary : direct NT system of drug action - ex. nicotine -> ACh system, Ketamine -> Gly system drugs are DIFFERENT in their primary effects/mechanism of action act on different NT systems |
| How do we quantify drug effects? (measure intended vs side effects at different doses) | Dose Response Curves |
| Describe the different parts of a dose response curve | threshold: dose that produces the smallest measurable response 50% effective dose (ED): dose that produces half the max effect 100% ED potency: amount of drug needed to produce an effect |
| How do we get potency from a dose response curve? | Put two different drugs on the same graph potency is the difference between the ED50 of the drugs (comparing ED50 of different drugs shows differences in potency even w/ identical efficacy) |
| How do we get efficacy from a dose response curve? | Put two different drugs on the same graph measure the difference bewteen their ED100 (vertical) |
| How do we measure safety in Dose-response Curves? | Therapeutic Index = TD50/ED50 (LD50 in animals) - margin of safety for humans = TD1/ED99 |
| How are Drug Induced Adaptions categorized (2 categories)? | Acute vs Chronic |
| Describe acute drug action | molecular changes produced by the drug when it binds - drug action, immediate, drug-dependent, altered neurotransmission |
| describe chronic drug action | lasting changes produced by the drug - from single OR repeated use -stays after drug is cleared -alters proteins in neurons STRUCTURAL & FUNCTIONAL change |
| What are the relevant proteins in drug induced adaptations? | ion channels, receptors (both types), transporters (reuptake), G proteins, other intracellular proteins |
| How can drugs alter receptors (4 ways)? | 1. decrease in efficiency 2. increase in efficiency 3. decrease in number 4. increase in number |
| Why do drugs alter receptors? | maintain "homeostasis" like thing --> compensatory responses |
| Describe 1st effect of drug induced changes (receptor desensitization) | decrease in efficiency - agonist --> more NT action / receptor activation --> reduced receptor response |
| Describe 2nd effect of drug induced changes (receptor sensitization) | increase in efficiency - decreased NT action/ antagonism -> enhanced response (less common) |
| Describe 3rd effect of drug induced changes (receptor downregulation) | decrease in number - agonist -> more NT action / receptor activation --> receptors are internalized (can occur w/ one dose_ --> can degrade (downregulation) (typically multiple doses) |
| Describe 4th effect of drug induced changes (receptor upregulation) | increase in number antagonist -> reduce NT action -> more receptors added |
| What 2 effects do receptor changes lead to | drug tolerance drug sensitization |
| What is drug sensitization and what does it mean? | an increase in a specific response to a specific drug dose following administration need lower dose to get original effect (often w/ side effects ie teeth chattering) |
| How can we measure sensitization/tolerance using dose response curves? | put the same drug on the same dose response curve measure the (horizontal) difference between ED50 increased sensitivity --> curve moves left increased tolerance --> curve moves right |
| What is drug tolerance and what does it mean? | a decrease in specific response to a dose of drug following administration need higher doses for the original effect |
| What are the 3 types of tolerance? | 1. metabolic tolerance 2. behavioral tolerance 3. pharmacodynamic tolerance |
| What neural mechanisms does tolerance include? | 1. receptor desensitization - receptor efficiency reduced -> need more agonist 2. receptor downregulation - fewer receptors available -> NEED MORE AGONIST 3. receptor upregulation - more receptors available -> NEED MORE ANTAGONIST |
| What is Cross tolerance? | when tolerance to one drug increases tolerance to other drugs |
| which mechanisms of tolerance does cross tolerance usually effect? | 1. metabolic tolerance: enzymatic 2. pharmacodynamic tolerance: receptor-mediated |
| Where does pharmacodynamics occur? | typically in circuit mediating primary drug effects can ALSO occur at secondary circuit |
| What did Volkow 1997/2007 find? | D2 downregulation associated with tolerance to rewarding effects of drugs even in detoxed users also generates cross-tolerance to natural rewards |
| Process of Drug induced adaptations? | neural adaptation - changes to primary receptors and secondary DA receptors lead to changes in physiological/psychological effects of drugs - sensitization/tolerance -reduced response to natural "rewards" (via DA) --> changes to Glu circuits in VTA |
| What is Hebb's Law? | "neurons that fire together, wire together" neural basis of change and learning "synaptic plasticity", long term potentiation |
| What is Long Term Potentiation (LTP)? | long term changes in synaptic sensitivity/excitability ("wiring") following stimulation ("firing") synapses: excitatory Glu synapses Changes: receptor proteins at the synapse Long term: hours to years |
| what does increased excitability in LTP mean? | increased likelihood of post synaptic cell firing an AP --> future stimulation leads to GREATER depolarization of post synaptic neuron |
| How do we induce LTP? (method using the toy model comparing LTP to non LTP) | 1. stimulate GLU axons 1 and 2, record potential in postsynaptic R1 and R2 (2x minute) 2. stimulation releases Glu from A1 and A2 3. stimulation causes EPSPs in R1 and R2 4. stimulation A1 repeatedly (100x min / tetanus) 5. A2 gets only 2x / min |
| What happens after tetanus of A1 in LTP? | during tetanus to A1, EPSPs in R1 intensify --> A1 and A2 evoke more EPSP in R1 than R2 = LTP |
| What causes LTP? | repetitive stimulus, strong stimulus OR two stimuli together (association) |
| What are the 4 major players in LTP? | Glutamate, AMPA receptors, NMDA receptors, Ca 2+ |
| What is the mechanism of LTP? | 1. Glu input at nearby AMPA -> depolarized 2. enough depolarization -> Mg 2+ out 3. If Glu binds to NMDA receptor... 4. Na+ & Ca 2+ ions flow inwards -> EPSP 5. Ca 2+ = 2nd messenger 6. lead to sensitization / insertion of AMPA receptors |
| What does LTP do to AMPA receptors? | Sensitization or Upregulation (leads to more EPSP) ->A/N ratio increases |
| On what receptor is LTP dependent? | NMDA |
| What does LTP need in order to occur? | 1 strong/repetitive/multiple/combined stimulations 2. release of glutamate 3. binding to AMPA 4.Sufficient excitation/depolarization of post-synaptic neuron 5. NMDA activation (Ca 2+ influx) |
| Early vs Late LTP? | Early: hours - rapid sensitization/insertion of AMPA late: sustained - local AMPA upregulation (protein synthesis) - Larger A/N ratio - greater effect of future glutamate input at same synapse -> more EPSPs -> more future firing Basis of learning |
| Neuron 1 releases glutamate. We use an electrode to measure EPSPs in neuron 2. Tetanus is applied to neuron 1. If you then stimulate neuron 1 again, what will likely happen to EPSPs in 2? | increase |
| Drug taking can influence the number of receptors in the neuronal membrane. What change is likely to occur with the administration of an agonist? How does this influence drug effects | downregulation tolerance-> need more agonist for the same effect |
| Where do addictive drugs primarily increase DA? How does that affect LTP? | VS / NAcc --> induce LTP on VTA DA neurons |
| What synaptic cleft does LTP act on? | PFC Glutamate neuron to VTA DA neuron |
| Describe Drug-induced LTP | NMDA receptor="coincidence detector"-needs strong/multiple inputs to activate Strong drug->PFC neuron release Glu->DA release Drug causes LTP from PFC->VTA light (at 1st) might depolarize but no AP/LTP->weak with BOTH->LTP for BOTH->light release DA |
| What does the Drug-induced LTP mean? | cues can become associated with drugs any stimulus can be associated with drugs predicts drug -> DA release in VS/NAcc "hyperlearned" associations = much stronger --> cue induced drug seeking |
| How does Drug-induced LTP show up in humans? | Drug predicting cue -> increase in DA drug predicting cue -> cue induced drug seeking -> creat an affective / motivation state |
| what is a craving? | a strong desire |
| what is a cue induced craving? | craving you feel after seeing drug cues (following drug use) |
| What did Carter and Tiffany 1991 study? | Cues -> craving |
| how do cues induce craving? | Cues -> DA in VS -> Craving (fMRI) drug causes increase in neural activity in the ventral striatum the more the cue activates the VS, the greater the craving |
| What does craving usual induce? | behavior (ie consumption) A MAJOR CAUSE OF RELAPSE |
| what are historical reasons humans take drugs? | exploration (curiosity, availability of fermented fruit), religious uses, medicinal uses (cures, poisons), once started... reinforcement! |
| In our current society, how do we start taking drugs? | Individual (biology, etc) < community and family (peers, schools, gangs, local police, etc) < societal (laws and penalties, availability, ads, portrayal in media, etc) |
| When does Drug use become problematic? | depends on the person (which, who, when where, why, etc) --> use vs misuse |
| what are some possible problems from drug use? | health / toxcitiy - short vs long term -drug induced / related -death / diseases accidents - physical harm - emotional harm (self/others) Crime - violence/theft life problems addiction ALL OF THESE from repeated use |
| What is DAWN? | drug abuse warning network sample medical record from a sample of hospitals |
| What is the disorder in the DSM V that characterizes Drug misuse? | Substance use Disorder (intoxication / withdrawal disorders) |
| What is a substance use disorder definition? | a problematic pattern of substance use leading to clinically significant impairment or distress as manifested by at least two of the following occuring within a 12 month period |
| What are the categories in a substance use disorder? | - Impaired control over substance use -social impairment - risky use of substance -pharmacological criteria (neural adaptation) |
| what are the effects that imply impaired control over substance use for a SUD in the DSM? | 1.taken in larger amounts/longer than intended 2. persistent desire/unsuccessful efforts to cut down/control drug use 3.great deal of time spent in activities to obtain,use,recover from drug 4.craving /strong desire to consume drug |
| what are the effects that imply social impairment for a SUD in the DSM? | 5.recurrent use resulting in failure to fulfill major role obligations 6. continued use despite having persistent/recurrent social/interpersonal problems caused 7. important social, occupational, recreational activities given up/reduce bc of drug |
| what are the effects that imply risky use of substance for a SUD in the DSM? | 8.recurrent drug use in situations in which it is physically hazardous 9.use is continued despite knowledge of having a persistent or recurrent physical/psychological problem likely caused/ exacerbated by drug |
| what are the effects that imply neural adaptation to substance for a SUD in the DSM? | 10.tolerance - need for increased amounts of drug to achieve intoxication/result -markedly diminished effect w/ continued use of same dose 11. Withdrawal -withdrawal symptom characteristic of drug -substance is taken to relieve/avoid wd symptoms |
| What are the stages in the SUD/Addictions Cycle? | Craving->intoxication -> bingeing-> withdrawal -> |
| What are the theories of addiction? | Khantzian Self Medication Hypothesis -drug choice isnt random social learning theory the reward-deficiency hypothesis(Volkow 2007) neural adaptations (south park theory) *Diathesis-stress model of addiction (combination) -predisposition x experience |
| What is the Diathesis Stress model of addiction? | First there is experimental drug use then interaction of: - genetic factors (vulnerability, gene x environment interaction) -environmental factors (social factors, alternative reinforcement) -personality factors |
| what personality factors are associated with addiction? | low self control (tested with delay of gratification task) impulsivity sensation seeking hopelessness anxiety sensitivity (neuroticism) |
| Neuron 1 produces/releases GABA. If Neuron 1 now releases GABA what will happen to EPSPs/IPSPs on Neuron 2? | IPSPs more likely (inhibitory, Cl-) |
| A competitive/selective GABA A antagonist was administered. If Neuron 1 now releases GABA what will happen to EPSP/IPSPs on Neuron 2? | IPSPs less likely (GABA can’t bind/activate) |
| Neurons 1&2 are in John’s brain. John started drinking alcohol daily for a week. What might happen to GABA A receptors on neuron 2? | Downregulation (decrease in number) |
| what drug factor affect addiction / reinforcing? | different drug (some more reinforcing / addictive than others) some routes more addictive |
| what are chronic effects of drugs? | alter synaptic transmission acutely - a primary mechanism, and 2nd MoA on DA alter key proteins chronically - receptor changes, drug tolerance / sensitization, LTP / cue-induced craving Posit interaction between subcortical regions and PFC |
| What are stimulants? | psychoactive drugs that produce a temporary increase in psychomotor activity (eg mental and/or physical function) |
| what are the main types of stimulants? | 1. xanthines 2. nicotine 3.Cocaine (% methylphenidate/ritalin) 4. amphetamines (including meth, mdma) 5. other/atypical stimulants |
| describe xanthines | family of naturally occurring stimulants often considered mild caffein, theophylline, theobromine Same mechanism of action |
| describe caffeine's pharmacokinetics | Route: oral, membranes, skin absorption: rapidly and completely from stomach and small intestine (30-60%) Distribution: significant blood levels - crosses BBB metabolism: by P450 enzyme CYP-1A2 (primary) |
| what are the Phase 1 metabolites for caffeine? | Paraxanthine, theobromine, theophylline (all active) |
| how is caffeine eliminated? | 95% metabolites (inactive, secondary), 2-5% unchanged, 95-98% urine |
| What is Adenosine? | A purine NT [intracellular (ATM, cAMP) ATP can be released from neurons] adenosine metabolized from ATP a neuromodulator |
| what is adenosine's functions? | adenosine makes you sleepy -> increases sedation (decrease during sleep_ |
| what are adenosine receptors? | 4 metabotropic (A1, A2A, A2B, A3) |
| describe Adenosine's A1 receptor | - A1 on axon terminals, inhibits voltage C12+ to open -inhibit NT release -A1 activation inhibits Glu,Ach, Da, Ne release |
| describe adenosine's A2 receptor | -A2A on GABA neurons (dendrites) --> excitatory on GABA --> Gs GPCR (increase cAMP) -> increase GABA release --> inhibits Flu, Ach, DA, NE |
| what is caffeine's mechanism of action? | competitive adenosine antagonist (non selective) caffein antagonizes adenosine's effect (reduced GABA release -> increases Glu, ACh, DA, NE -> indirect agonist) DISINHIBITION of DA, NE, ACh, Glu |
| does caffeine preferentially increase DA in VS? | NO, also in DS, PFC (mostly) |
| With larger doses only, what are the other primary mechanisms of caffeine | inhibition of PDE direct blockade of GABA A Ca 2+ release |
| What are caffeine's effects with lower doses (50-200 mg) | depends on dose, prior use, tiredness alertness (if tired), possibly mild euphoria - enhance sports endurance and attenntion -improves simple tasks but can decline w/ higher doses -reverses fatigue-induced decrements in performance |
| What are caffeine's effects long term | lower death/heart problems lower rate of Type 2 diabetes protective of parkinson's, alzeimer |
| What are caffeine's effects with larger doses | agitation, anxiety, sleep disturbance, hypertension ,jitteriness concerns: - Intoxication, caffeine induced disorders, toxicity |
| What are the effects of caffeine on sleep | sleep disruption sleep latency increased and total sleep time decreased with subjective reports remaining unchanged |
| What's in a cigarette? | tobacco leaves, nicotine*, 600 additives, 4000 compounds in smoke |
| Nicotine Pharmacokinetics? | Route:typically inhalation -enters lunch on tar particles -controllable absorption: through lung membrane 9tar stays) distribution: mere seconds nicotine to brain (high addictive potential) |
| nicotine pharmacokinetics of metabolism? | primary liver P450: CYP 2A6 (minor: 1A2, 2E1) |
| nicotine pharmacokinetics of elimination? | 70-80% cotinine, 5-10% unchanged |
| Nicotinic ACh Receptors? | - alpha and beta subunits(12 known a2-10, b2-4) -three main types in CNS - a7 nAChR subtype (low nic affinity) - a6B2B3 nAChR subtype - a4b2 nAChR subtype (lhigh affinity) -reinforcing effects -fast excitation (Na+ & Ca2+) (also K+) |
| what is nicotine's mechanism of action? | stimulant full selective, competitive Acetylcholine agonst at nicotinic receptors with reinforcement through a4b2 nAChR biphasic effect activation-> rapid desensitization agonist-> antagonist-like |
| what are the phases of nicotine's MOA? | 1. agonist / excitatory 2. no longer activates nAChR -> rapid desensitization (no longer open) -> functional antagonism |
| what is nicotine's secondary MOA? | indirect DA agonist, indirect Glu agonist (-> DA/5HT agonist) |
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minalogy