Exam 1 Flashcards
Drug
a substance that is used primarily to bring about a change in some existing process or state
Psychoactive drug
changes brain function and results in alterations in perception, mood, or consciousness
what substances were used by ancient people?
nicotine, caffeine, morphine, cocaine, and THC
Neuropsychopharmacology
influence of drugs on brain, behavior, and psychological function
4 ways to classify drugs
- Source (natural, synthetic, semisynthetic)
behavioral/ psychological effects (medical/therapeutic use) - Pharmacological action (ex: things that act on GABA)
- Chemical structure
- Legal status
Addiction
- craving, relapse, chronic, inability to control drug use, use despire harm, social/interpersonal problems
- kown as substance use disorder
- NOT physical dependence and withdrawal
Physical dependence
body relies on drug to prevent withrawl due to PHYSIOLOGICAL ADAPTATIONS
craving and relapse are persistent
Binge drinking in men vs women
men: 5+ drinks,
women 4+ drinks
heavy drinking
5 or more binge days out of last 30
what factors shaped drug use and cultural attitudes in the US?
- alcohol temperance moment
- increased addictive potential of drugs due to advances in chemistry and development of syringes
- increased drug availability and luck of drug control law
- medicalization of drug addiction
Anti-Drug Abuse Act of 1986
- increased penalties for drug crimes
- Created big racial sentencing disparity between crack (black) and powder (white) cocaine
Bioavailability
amount of drug available to bind to target sites and illicit drug action
Pharmacokinetics
- absorption, distribution, metabolism, and excretion of drugs (movement)
- affect drug onset, duration, and peak concentration
Pharmacodynamics
biochemical effects of drugs and their mechanism (change in body); action of drug at receptors or targets
what affects absorption?
- route of administration (blood circulation and surface area at site of administration, amount of drug destroyed by digestive/ metabolic processes, transport across membrane)
- drug solubility and ionization
what does fast onset and high peak concentration mean?
short duration
oral (po)
- absorption in gastrointestinal tract (enteral route)
- slow variable (affected by food)
- must be resistant to stomach acids and enzymes
- first-pass metabolism in the liver before entering bloodstream
Slow route; slow absorption
Intranasal
substance does not need to be dissolved (bypasses BBB straight into olfactory bulb)
Sublingual
absorbed by mucous membranes in mouth
Used for rapid adjustment for pain levels
Rectal
absorbed by blood vessels
Injections
- Subcutaneous (SC, sub-Q)
- Intramuscular (IM)
- Intravenous (IV)- rapid and accurate
IV: fast onset; used for abuse
what is distribution and what affects it?
movement from blood to target site (brain)
1. BBB
2. depot binding
BBB
blood brain barrier
selectively permeable (lipophilic) to keep brain environment stable and keep bacteria/viruses out
1. typical capillaries: “leaky”, allow ionized molecules in/out
2. brain capillaries: more selective but lipid-soluble drugs (like psychoactive drugs can still diffuse through)
Depot binding
- drug affects peak and duration of drug concentration
- Drug remains in system in inactive state, so it is protected from metabolism
first order kinetics
drugs cleared at exponential rate based on half life
zero-order kinetics
drugs cleared at (constant) linear rate because metabolism/excretion processes are saturated
ex: alcohol
The law of mass action
- More drug molecules = increased receptor occupancy.
- Maximum drug effect = when all receptors are occupied
- The cellular response is proportional to the degree of receptor occupancy.
- Relationship is described by the dose-response curve
ED50 vs ED100
ED50: Dose that produces half the maximum effect
ED100: Effective dose that gives maximum response; adding more drug does not increase the observed drug effect because all receptors are occupied
TD50 vs LD50
TD50: dose that produces a given toxic effect in 50% of subjects
LD50: dose that kills 50% of subjects (lethal dose)
Therapeutic Index
aka margin of safety
= LD50/ED50
Potency vs efficacy
potency: amount of drug needed to produce an effect
efficacy: maximum effect that can be produced by a drug
what antagonists can be overcome by adding more?
competitive
PAM vs NAM
PAM: amplify primary ligand effects
NAM: reduce primary ligand effects
Tolerance vs acute tolerance (tachyphylaxis)-
tolerance: Drug effect decreases with repeated administration
acute: drug effect decreases rapidly within a single session (ex: alcohol produces greater behavioral deficits when blood level (BAC) is rising vs. falling
Sensitization and cross-sensitization
sensitization: less drug is required to get same effect (shifts dose-response curve to the left)
Drug effect increase with repeated administration
cross: drug effect increases due to repeated administration of another drug
mechanisms for tolerance/ sensitization
- pharmacokinetic (changes in metabolism)
- pharmacodynamic (changes in receptors and their corresponding signaling pathways)
- behvioral
what causes action potentials?
when local potentials are large enough and there is sudden rush of Na+ ions into the axon
what does a cell at rest look like?
- Cell is polarized (different charge between inside and outside the cell)
- K+ channels are open (creates resting potential)
- Na+ and Ca+ channels are closed
- Cl- channels are closed
How can ion channels open?
- Ligand binding (ligand-gated ion channel/ ionotropic receptor)
- Change in membrane potential (voltage-gated ion channels)
- Intracellular signals: (phosphorylation, G- proteins)
EPSP vs IPSP
EPSP: Na+ channels open; depolarization
IPSP: Cl- or K+ ion channels open; hyperpolarization
Postsynaptic effects by different types of synapses
Axodendritic and Axosomatic: singaling cascade and open ion channels by EPSP and IPSP
Axoaxonic: signaling cascade and open ion channels by changing NT release
Classical Neurotransmitters
- types: amino acids, monoamines, acetylcholine, purines
- made from dietary precurosors that cross the BBB
- made in axon terminal and transported into small vesicles and remain there because they are ionized and cant cross membranes
- require active trnsport into vesicles via vesicular transporters
types of non-classical neurotransmitters
neuropeptides, lipids, and gasses
how are neuropeptides made?
made in cell body, packaged into large vesicles, and transported down the axon (protein-synthesis depenent)
Vesicular transporters
- move transmitters into vesicles
- Vesicle fusion with cell membrane is mediated by SNARE proteins
- Botulinum toxin cleaves SNARE proteins involved in vesicle fusion
Vesicle recycling
new (empty) vesicles can be refilled with NT rapidly
Autoreceptors
receptors on the same neurons releasing the neurotransmitter and provide feedback (negative)
terminal: modulate NT release
somatodendritic: modulate NT release/ firing
Neurotransmitter inactivation
- Enzymatic degradation(metabolism via enzymes)
- Plasma membrane transporters: nerve terminal (reuptake) or glia (remove NT from cleft)
Retrograde transmission
- signaling from postsynaptic to presynaptic cell
- Gasses and lipids pass through membranes and signal to presynaptic terminals. NO VESICLES
ionotropic receptors
- open when ligand binds (direct IPSP/ EPSP)
- 4-5 subunits bound together to form ion channel
- fast, easily reversible
- ex: nAChR gates cation channel// GABAa gates a Cl- channel
Metabotropic Receptors
GPCRs
- indirect
- 1 subunit with 7 transmembrane proteins, coupled to intracellular G protein
- slower effects
- G-protein gated ion channels and second messenger systems
Second messenger systems
- Gs, Gi, Gq proteins: a and by subunits
- second messengers
- protein kinases
- gene regulation (through transcription factors)
immediate early genes (IEG)
the first genes to be transcribed into mRNA and then translated into protein quickly
* c-FOS: marker of neural activation (like after you administer a drug)
difference between Gs and Gi proteins
Gs: interact with D1 receptors and excite cell
Gi: intect with D2 receptors and inhibit cell
Connectome
comprehensive map of connections within nervous system
types of animal tests/ paradigms for uncoditioned behavior (and what they measure)
- simple behavioral observation (eating, tremors, sleep)
- motor activity (measures horizontal and vertical movement)
- analgesia (tested by tail flick and hot plates)very highly predictictive
- anxiety (elevevated plus maze records amount of time that rodents spend in bright exposed area) (light-dark box and open field measure anxiety by seeing avoidance of bright exposed places)
Types of animal tests/ paradigms for classical conditioned behavior
- fear conditioning (test of learning and remembering emotional events)
- conditioned place preference
Types of animal test/paradigms for conditioned behavior: instrumental
conditioning
(Skinner)
- maze learning
- operant chamber learning (drug administration, self- administration, and addiction potential)
How do we test a drug for stimulus, rewarding, and reinforcing properties?
stimulus: drug discrimination (T maze)
rewarding: conditioned place preference
reinforcing/ incentive: self-administration
what are FR, VR, and PR schedules of reinforcement?
FR: fixed ratio; reinforced after every nth response
VR: variable ratio; reinforced on average every nth reponse (mean)
PR: progressive ratio; each reinforcement requires more reponses
FR-5 = reinforce every 5 responses
VR-5= reinf after 13579 (mean is 5)
PR= reinforced after 1 response, then 2,4,5,9,12,15,20
How are fixed and progressive ratio different in dose-response curves?
FR: inverted U shape (less reponding at high drug doses because of satiety)
PR: only increases
what measures of “addiction” are measured in newer animal models?
- escalation of use
- difficulty stopping
- continuted use despite negative consequences (resistance to punishment)
- use to the exclusion of other behaviors
neuropharm techniques that are used to measure/ detect receptors? proteins? mRNA?
d
what is hybridization use for?
to visualize mRNA
In vitro vs. In situ vs. In vivo
in vitro: in a dish (more exact quantificcation); tissue extract
in situ: in place; tissue slice
in vivo: living organism
Which techniques can be used in live humans? Which techniques are non-invasive?
noninvasive:
1. EEG- voltage changes (high time, low spatial)
2. fMRI- blood flow changes (low spatial, high time)
invasive: electrophysiology
Which techniques require intracranial manipulation?
electrophysiology: record electrical signals from neurons
neurotransmitter detection: measure neurotransmitter levels
lesions: ablate/remove certain brain areas
local drug delivery: inject drug into specific brain area
aka stereotaxi
microdyalisis/ voltammetry
used in freely-moving animals to measure NT levels and see how they change over time
immunohistochemistry
binding of specific antibodies to visualize the location of proteins
primary antibody: binds to protein of interest
secondary: binds to primary
label: colored product from enzyme reaction, fluorescence
CLARITY procedure: dissolves lipids/fats. no sectioning of brain. Whole brain cellular architecture
What is a lesion? Types of lesions?
genereal neurotoxin lesions: ex: NMDA is toxic to all neurons
specific neurotoxin lesion: ex: 6-OHDA is toxic only to catecholamine neurons
Types of genetic manipulation techniques
- mutations (knockouts, knockins, transgenic)
- gene silencing (RNA interference)
- gene editing (CRISPR-Cas9)
- viral vectors (replication-disabled viruses)
Types of mutants
- knockout- remove gene (loss of function)
- knockin- replace gene (gain function)
- transgenic- introduce new gene
What is optogenetics?
- incorporate light-gated ion channels and pumps into neurons
- allows depolarization/hyperpolarization of cells using light
CS
US
UR
CR
CS: tone
US: shock
UR: activity burst, vocalization
CR: freezeing (and suppression of feeding)
Conditioned place preference testing, advantages, and disdvantages
- testing for reward
- animal is confined to one side of the box after drug injection and to other other with control injection. Testing to see where they spend time when they have access to both sides)
- if drug is rewarding: will spend more time in drug-paired side and show conditioned place preference (CPP)
- if drug is averside: will avoid the drug-paired side and how conditioned place aversion (CPA)
self-administration
aka operant, instrumental, or skinner conditioning
response elements: levers, nosepokes
rewards: food, water, drug
aversive elements: footshock in grid floor
stimuli: lights, tones
“will you work for the drug”
