Exam 1 Flashcards
pharmacology
uses, effects, and modes of actions of drugs
psychopharmacology
Influence of drugs on behavior and psychological function
neuropharmacology
Influence of drugs on brain function
neuropsychopharmacology
Influence of drugs on brain, behavior and psychological function
psychoactive drug
chemical substance that alters perception, mood, or consciousness
purposes of psychoactive drugs
recreational, ritual/spiritual, therapeutic
classification by source
natural, synthetic, semisynthetic
classification by behavioral/psychological effects (5)
stimulants, depressants, analgesics, hallucinogens, psychotherapeutics
classification by pharmacological action
often drugs have multiple pharmacological actions, so it’s difficult to classify
other ways to classify drugs
chemical structure, legal status
what terms have been synonymous with addiction?
dependence and drug abuse
physical dependence
body relies on drug to prevent withdrawal
addiction
- uncontrollable cravings
- inability to control drug use
- compulsive drug use
- use despite doing harm to oneself or others
- classified as a disease
in the last month, __% of the U.S. population has used illicit drugs
13
most common illicit drug used in the U.S.
marijuana
age group in which drug use is most common
young adults (18-20)
percentage of people with substance use disorder
14.5% (40.3 million people)
most common substance abused & diagnosed
alcohol
binge drinking
at least 5 drinks in one session for men; at least 4 drinks in one session for women
heavy drinking
at least 5 binge days out of last 30 days
daily marijuana use has ___ among college students
increased
binge alcohol use is ___ in college students than in non-college peers
greater
marijuana and nicotine vaping are ___ among college students
increasing
illicit drug use in high school students
- steady in 12th graders over the years
- decreased alcohol use across all grades over the last decade
cigarette use in high-school students has ___ over the last 10 years
decreased
nicotine and THC vaping have ____ in high-school students
increased
psychoactive substances used throughout history (5)
nicotine, caffeine, morphine, cocaine, and THC
alcohol temperance movement’s effects on attitudes towards drugs/alcohol
did not outlaw alcohol, but drug use in general was socially unacceptable
prohibition
alcohol is outlawed and seen as criminal behavior
scientific advancements that led to greater drug use
increased addictive potential of drugs and development of hypodermic syringes
approach to drug control that led to increased drug use
increased drug availability and lack of drug control laws
changes in treatment of addiction
medicalization led to categorizing addiction as a disease
effects of Nixon’s War on Drugs in 1971
expanded incarceration, drug crimes more severely punished and policed
targets of the War on Drugs
Black population, anti-war left
effects of the War on Drugs in the 80s
mandatory minimum prison sentences, increased penalties for posession
Anti Drug-Abuse Act of 1986
created a big sentencing disparity between crack and powder cocaine, which further fueled racial disparities in incarceration
top consumer of illicit drugs in the world
USA
race typically subjected to higher rates of arrests and incarceration
Black population
past approach to the war on drugs
- viewed drugs as a criminal justice problem
- law enforcement
- penalization
science’s influence on drug policy
little to none
what method is effective when tackling a drug problem
treatment programs
future of war on drugs
- drugs are a public health problem
- increased treatment availability
- focus on education, prevention
- reduced drug sentences
- legalization of marijuana
- harm reduction (syringe programs)
DSM-5 definition of substance use disorder
significant impairment in at least 2 categories in a 12-month period: impaired control, social impairment, risky use, pharmacological properties
changes from DSM-I to DSM-V when discussing addiction
gradual transition from stigmatizing to biological basis
addiction is NOT
physical dependence and withdrawals
addiction IS
craving and relapse
definition of addiction
chronic, relapsing brain disease characterized by compulsive drug seeking/use, despite harmful consequences, major impairment to self-control
bioavailability
amount of drug available to bind to target sites and elicit drug action
absorption
movement from site of administration to blood circulation
oral route of administration
- aka preoral, PO
- absorption in the GI tract
- slow, variable
- undergoes first-pass metabolism in the liver before entering the bloodstream
first-pass metabolism
aids in drug degradation and sometimes drug design
routes of administration that typically avoid first-pass metabolism
intranasal (bypasses BBB), inhalation, sublingual, rectal, transdermal
injection routes of administration
subcutaneous, intramuscular, intravenous (IV)
factors affected by route of administration
onset, peak concentration, and duration
slow route of administration
typically for medical use, longer duration
fast route of administration
typically associated with drug use/abuse, used to achieve highest peak concentration with rapid onset
oral and transdermal administration
slow absorption
intravenous injection or inhalation/smoking (route of administration)
rapid drug entry, fast onset
increased addictiveness is associated with…
fast onset and short duration
how route of administration affects absorption rate
- blood circulation and surface area
- amount of drug destroyed by digestive or metabolic processes
- transport across membranes
drug properties that affect absorption rate
solubility, ionization
most drugs easily diffuse across membranes when they are
lipid-soluble, non-ionized
lipid solubility of heroin vs morphine
heroin reaches the brain much faster than morphine because of increased lipid solubility
drug ionization
occurs when drugs are dissolved in water (neutral pH) due to them being a weak acid or base
lipid solubility of ionized drugs
not readily lipid soluble, making diffusion difficult
factors affecting drug ionization
different bodily fluids (different pH)
ion trapping
concentration of drug in one compartment
distribution (ADME)
movement from blood to target site
factors affecting distribution
depot binding and the blood-brain barrier (BBB)
blood-brain barrier
selectively permeable (lipophilic) to keep a stable brain environment
weak BBB areas
area postrema, median eminence
depot binding
can occur in albumin (plasma), fat, and muscle, where the drug remains in an inactive state in the system and is protected from metabolism
factors affected by depot binding
peak concentration and duration of drug concentration
example of depot binding
THC: depot binding in fat leads to slow release, making THC detectable in urine days after the initial dose
metabolism and excretion (ADME)
movement out of the system
drug inactivation (biotransformation)
usually by metabolism, occurs in the liver by microsomal enzymes
phase I metabolism
oxidation, reduction, or hydrolysis (non-synthetic)
phase II metabolism
- addition of small molecules (glucuronide, sulfate, methyl groups (synthetic)
- products ionized and less lipid soluble so they become inactive metabolites
active metabolites
- have biological activity of their own
- need further metabolism to become inactive metabolites
drug clearance: first order kinetics
- drugs cleared at exponential rate
- based on half-life
- most common
drug clearance: zero-order kinetics
- drugs cleared at constant rate (linear)
- example: alcohol
individual variation in drug metabolism
- sex differences
- individual adaptation (tolerance)
- age effects
- genetic differences
drug therapy for alcoholics (Disulfram/Antabuse)
blocks ALDH
pharmacokintetics
how drugs move throughout the body
pharmacodynamics
- how drugs affect the body
- actions of drugs at receptor sites
ligand
neurotransmitter or drug that fits a given receptor
receptor
protein a ligand interacts with to initiate biological effects
drug + receptor =
drug effects
agonists
ligands that bind to a receptor to initiate a cellular response
antagonists
- ligands that bind to a receptor to block the action of an agonist or endogenous ligand at the same receptor
- do NOT reverse the effects of an agonist or cause an opposite reaction
receptors are bound at the ___ of the cell
membrane
a drug can be ___ specific for the receptor than the endogenous neurotransmitter
more
T/F: drugs can show agonist or antagonist actions
T
drug-receptor interaction
modulate normal neuronal functioning by mimicking, increasing, or inhibiting normal physiological/biochemical processes
characteristics of drug-receptor binding
temporary and reversible
binding affinity
determines speed of dissociation
law of mass action
- more drug molecules = increased receptor occupancy
- maximum drug effect = all receptors occupied
- cellular response proportional to degree of receptor occupancy
dose-response curve
relationship between cellular response and receptor occupancy
reversibility of drug-receptor interactions
- most are reversible
- some form long lasting, irreversible bonds
ED100
- effective dose that gives maximum response
- all receptors occupied
- giving more of the drug does not increase observed drug effect
ED50
dose that produces half the maximum effect
dose-response curve shape
sigmoid
therapeutic index
evaluates all desirable and undesirable drug effects
TD50
dose that produces a given toxic effect in 50% of all subjects
LD50
dose that kills 50% of subjects (lethal dose)
therapeutic index (TI, margin of safety)
LD50 / ED50
potency
amount of drug needed to produce an effect
efficacy
maximum effect that can be produced
factors that affect potency
- pharmacokinetics
- binding affinity for certain receptors (does not determine maximum possible effect however)
factors that affect efficacy
- act by different mechanisms (different receptors)
- different activity at the same receptor
competitive antagonists
- bind to the same receptor binding site as agonist
- shifts DRC for agonist to the right
- antagonist effect can be overcome by adding more agonist
non-competitive antagonists
- do not compete with agonists for receptor binding site
- shifts DRC to the right for agonist, but also changes shape
- cannot be overcome by adding more agonists, there is a decrease in maximum effect
partial agonists
- efficacy is lower than full agonist, higher than antagonist
- in the presence of a full agonist, they act as antagonists
inverse agonists
- bind to receptors and initiate a cellular response that is opposite to the agonist
- descending DRC
allosteric modulators
ligands/drugs that indirectly influence the effects of a primary ligand
positive allosteric modulators (PAMs)
amplify primary ligand effects
negative allosteric modulators (NAMs)
reduce primary ligand effects
tolerance
- drug effect gets smaller
- more drug required for same effect
- DRC shifts to the right
sensitization
- drug effect gets bigger
- less drug required for same effect
- DRC shifts left
acute tolerance
- aka tachyphylaxis
- drug effect decreases rapidly within a single session
example of acute tolerance
when blood-alcohol level is rising vs falling
cross-tolerance
drug effect decreases due to repeated administration of another drug
cross-sensitization
drug effect increases due to repeated administration of another drug
pharmacokinetic (metabolic) mechanism of tolerance/sensitization
- changes in metabolism
- enzyme induction
pharmacodynamic mechanism of tolerance/sensitization
- changes in receptors and corresponding signaling pathways
- change in receptor number/sensitivity
behavioral mechanism of tolerance/sensitization
- changes due to learning factors
- can be context-specific
pavlovian/classical conditioning
conditioned stimulus (CS) training can contribute to sensitization or tolerance effects depending on conditioned reactions (CR)
context-specific tolerance/sensitization
tolerance/sensitization effects only expressed in a specific environment that was previously paired with the drug
context-specific tolerance related to heroin
this type of tolerance contributes to fatal heroin overdoses
signals sent within a neuron
electrical local and action potentials
signals send between neurons
chemical signals transported via neurotransmitters
post-synaptic potentials
local changes in electrical activity at the dendrites/input zone
action potentials
generated down the axon if a post-synaptic potential is large enough to reach the soma, all-or-nothing
resting membrane potential
difference in electrical charge inside vs. outside the cell (polarized)
ions
electrically charged molecules
ions
electrically charged molecules
anions
negatively charged
cations
positively charged
movement of potassium (K+) in a neuron at resting membrane potential
electrical pressure to enter the cell, but chemical pressure to leave the cell
movement of sodium (Na+) in a neuron at resting membrane potential
electrochemical pressure to enter the cell
movement of calcium (Ca2+) in a neuron at resting membrane potential
electrochemical pressure to enter the cell
movement of chloride (Cl-) in a neuron at resting membrane potential
chemical pressure to move out of the cell
triggers that can open an ion channel (4)
- ligand binding
- change in membrane potential
- phosphorylation
- G proteins
inhibitory post-synaptic potential (IPSP)
Cl- or K+ ion channels open, making the cell more negative
excitatory post-synaptic potential (EPSP)
Na+ ion channels open, making the cell more positive
threshold for an action potential
around -40 mV
what happens during an action potential?
membrane potential reverses (inside of cell becomes positive)
an action potential is caused by a rush of ___ ions into the axon
Na+
hyperpolarization is the same as…
IPSP
depolarization is the same as…
EPSP
function of voltage-gated Na+ channels
conduct the action potential down the axon
synapse
site of action for most psychoactive drugs
axoaxonic synapse (pre-synaptic facilitation/inhibition)
- open ion channels → affect NT release
- signaling cascade → protein function
axodendritic and axosomatic synapse
- open ion channels → EPSP, IPSPs
- signaling cascade → protein expression or function
presynaptic side of synapse
axon terminal contains synaptic vesicles that contain neurotransmitter
postsynaptic side of the synapse
Receptors respond to the neurotransmitters
classical neurotransmitters (4)
- amino acids
- monoamines
- acetylcholine
- purines
non-classical neurotransmitters (3)
- neuropeptides (opioids)
- lipids (endocannabinoids)
- gases
retrograde neurotransmitters
lipids and gases
examples of amino acid neurotransmitters (2)
glutamate and GABA
examples of monoamine neurotransmitters
DA (dopamine), NE (norepinephrine), 5-HT (serotonin)
steps in chemical synaptic transmittion
- synthesis
- release
- inactivation
synthesis of classical neurotransmitters
- synthesized from dietary precursors
- enzymes in axon terminals synthesize NTs
- then transported into small vesicles (~40 nm radius)
synthesis of neuropeptides
synthesized in cell body → packaged into large vesicles → transported down the axon
neuropeptide synthesis is dependent on ___
protein-synthesis
neurons that release neuropeptides can also release ___
classical neurotransmitters
classical NTs require ___ transport
active
vesicular transporters
move transmitters into vesicles
steps for NT release
- action potential reaches terminal
- activation of voltage-gated calcium channels
- influx of calcium
- calcium mediates fusion of vesicle
- NT is released via exocytosis
SNARE proteins
mediates vesicle fusion with the cell membrane
Botulinum toxin (Botox)
cleaves proteins involved in vesicle fusion
endocytosis
Vesicle membrane is retrieved from the terminal membrane
vesicle recycling
New (empty) vesicles can be refilled with NT rapidly
NTs rapidly diffuse across narrow synaptic cleft and bind to receptors in vicinity, including on:
post-synaptic neuron
There is also significant “spillover” at most synapses, or diffusion out of the cleft to reach receptors (3) on:
- presynaptic neuron (autoreceptors)
- astrocytes (glia)
- nearby synapses
autoreceptors
receptors on the same neuron releasing the NT and provide feedback (usually negative feedback)
terminal autoreceptors
modulate NT release
somatodendritic autoreceptors
modulate NT synthesis or firing
inactivation of NT via:
- enzymatic degradation (metabolism via enzymes)
- Plasma membrane transporters present in nerve terminal (2, reuptake) or glia
retrograde transmission
- Signaling from post-synaptic to pre-synaptic cell
- different than anterograde transmission used in most signaling
drug-receptor interactions
Drugs primarily act outside the cell on targets (receptors) on the cell membrane
receptor activation
activated by the binding of ligand (neurotransmitter, drug)
categories of neurotransmitter receptors
ionotropic and metabotropic
ionotropic receptors
- ligand-gated ion channels
- 4-5 subunits (separately encoded proteins) bound together to form an ion channel
- fast, rapidly reversible
metabotropic receptors
- G-protein coupled receptors
- use second messengers to open an ion channel or trigger cellular changes
- 1 subunit with 7 transmembrane domains coupled to intracellular G protein
- slower, long lasting
nAChR
- aka nicotinic acetylcholine receptor
- gates a cation channel
GABAa
gates a chloride ion channel
second messenger system - sequence
- activation of G protein
- change in activity of effector enzyme
- change in second messenger levels
- activation of protein kinase
- phosphorylation of of a substrate protein
families of G proteins
- α subunit
- βγ subunit complex
α subunit
Gs (stimulatory), Gi (inhibitory), Gq (quirky?)
all neurotransmitters have _____ receptors, but only some utilize _____ receptors
metabotropic, ionotropic
receptors that utilize ionotropic receptors
glutamate, GABA, acetylcholine, and serotonin (only one)
receptors determine whether effects are ____ or ____
excitatory, inhibitory
calcium regulation
tightly regulated due to playing a large part in neuronal function
protein kinase
modify other proteins by adding phosphate groups to them (phosphorylation).
protein kinase targets
ion channels, receptors, cytoskeletal proteins, transcription factors, etc.
protein phosphatastes
dephosphorylate proteins
phosphorylation
changes the structure/function of a protein to activate or inhibit
transcription factors
- family of proteins that bind to regulatory sites on genes to promote or suppress transcription of DNA to mRNA.
- activation can cause second messengers to alter gene regulation
immediate early genes (IEGs)
- first genes to be transcribed into mRNA and then translated into protein quickly
- include transcription factors
c-Fos
- a transcription factor and immediate-early gene
- marker of neuronal activation
epigenetics
can potentially change gene expression for a lifetime
unconditioned animal behavior
- simple behavior observation
- motor activity
- analgesia
- anxiety
locomotor activity chamber
measures horizontal and vertical movement using infrared beam breaks
analgesia tests
tail flick and hot plate tests measure reduced pain sensation (analgesia)
elevated plus maze test
used to measure anxiety
light-dark box and open field
both measure anxiety
classical conditioning examples
fear conditioning, conditioned place preference
instrumental conditioning examples
operant chamber learning
fear conditioning
test of learning and remembering emotionally aversive events
drug discrimination
used to assess stimulus properties, “what does the drug feel like?”
drug discrimination test findings
- animals classify drugs just like humans
- predictions have been highly sensitive and accurate
reward
something that is “wanted” or “liked,” drives appetite behavior
positive reinforcement
when adding something increases the probability of a behavior
negative reinforcement
when removing something increases the probability of the behavior
conditioned place preference
- used to assess rewarding properties
- do you “like” the drug?
conditioned place aversion
occurs when the drug is aversive and causes the animal to avoid the context they were in when given the drug
drug self-administration
- measures whether subject wants the drug and whether they will work for it
drugs that do not maintain self-administration
most hallucinogens (aspirin, LSD, mescaline, etc)
fixed ratio schedule
reinforced after every nth response
variable ratio schedule
reinforced on average after every nth response
progressive ratio schedule
each reinforcement requires more responses
cocaine self-administration in rats
rats will adjust rate of cocaine self-administration according to dose
dose-response curve of fixed-ratio schedule
inverted U shape
drug satiety
may explain why replacement therapy works
breakpoint (progressive ratio schedule)
- highest ratio attained before the animal “gives up.”
- measure of drug motivation.
- “How hard are you willing to work for the drug?”
rate of responding changes with dopamine antagonist
DA antagonist will increase FR responding and decrease PR responding
dose-response curve for progressive ratio schedule
just increases (not inverted U shape)
ligand binding
used to visualize receptors
antibody binding
used to visualize proteins
hybridization
used to visualize mRNA
tissue extract
provides quantification; in vitro
tissue slice
provides localization; in situ
living organism
in vitro
autoradiography
radioligand (radioactive ligand) shows location and density of receptors
autoradiography with PET
used to visualize receptors in live human brains (in vivo), injected intravenously
striatum
high concentration of dopamine receptors
immunohistochemistry
binding of specific antibodies to visualize location of proteins
primary antibody
binds to protein of interest
secondary antibody
binds to primary antibody
label (immunohistochemistry)
colored product from enzyme reaction
CLARITY
- ‘dissolves’ fats/lipids
- no sectioning of the brain, whole cellular brain architecture
in situ hybridization (ISH)
complementary RNA/DNA probes bind to mRNA
advantages of static visualization techniques
high specificity, full brain coverage, high spatial resolution
electroencephalogram (EEG)
non-invasive, good time resolution, poor spatial resolution
functional magnetic resonance imagine (fMRI)
non-invasive, detects blood flow changes
techniques requiring intracranial surgery
electrophysiology, neurotransmitter detection, lesions, and local drug delivery
another term for intracranial surgery
stereotaxic
stereotaxic surgery
allows for accurate targeting of specific brain structures
intracranial electrophysiology
record activity from (and stimulate) neurons in specific brain areas
microdialysis / voltammetry
can be used in freely moving animals to measure neurotransmitter levels and see how they change over time
common property in addictive drugs
evoke dopamine release in the ventral striatum (nucleus accumbens, NAc)
why do we need manipulation of variables in an experiment?
- to determine causation
- determine whether a specific brain area is necessary for a certain behavior
- is it necessary or sufficient for a drug effect?
- where in the brain is the drug rewarding?
- can we block the effects?
general neurotoxin lesion example
NDMA, toxic to all neurons
specific neurotoxin lesion example
6-OHDA toxic only to catecholamine neurons
local drug delivery (intracranial manipulation)
drug gets microinjected into a specific brain area of an awake animal
genetic manipulation techniques
- mutations
- gene silencing
- gene editing
- viral vectors
3 different kinds of mutants (usually mice)
- knockout
- knockin
- transgenic
knockout (genetic mutation)
removal of a gene, loss of function
knockin (genetic mutation)
replace gene, gain of function
transgenic (genetic mutation)
introduce new gene
gene silencing
performed via injection of RNA interference
gene editing
performed via CRISPR-Cas9; can remove, replace, or add DNA
viral vectors
- used for gene therapy in humans
- replication-disabled viruses that can infect cells, integrate into the host genome and cause stable expression of introduced genes
optogenetics
- incorporate light-gated ion channels and pumps into neurons
- allows depolarization/hyperpolarization of cells using light
