Neuro of Drug Addiction Exam 1

What is a drug?

-a substance that is used “primarily to bring about a change in some existing process or state, be it psychological, physical, or biochemical”

-”chemical entity, or mixture, other than those providing maintenance of normal health (eg food) that alters biological functioning”

-food effects studied by nutritionists and appetitive neurobiologists

Pharmacology

the branch of medicine that deals with the 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 (our perspective in this class)

How are drugs classified/named?

-by source

-therapeutic use

-mechanism of action

-chemical structure

-legal/social status

T/F: synthetics can be far more potent than naturally-occurring drugs

TRUE

CNS Stimulants

-makes you more awake

-amphetamine, cocaine, nicotine

CNS Depressants

-makes you sleepy

-barbiturates & alcohol

Analgesics

-for pain relief

-morphine & codeine

Hallucinogens

mescaline, LSD, psilocybin

Psychotherapeutics

prozac & thorazine

Schedule 1

-substances that have no accepted medical use in the US and have high abuse potential

-heroin, LSD, mescaline, marijuana, THC, MDMA

Schedule 2

-substances that have a high abuse potential with severe psychic or physical dependence liability

-opium, morphine, codeine, cocaine

Schedule 3

-substances that have an abuse potential less than those in schedules 1 and 2, including compounds containing limited quantities of certain narcotics and nonnarcotic drugs

-paregoric & other barbituates

Schedule 4

-substances that have an abuse potential less than those in schedule 3

-diazepam & xanax

Schedule 5

-substances that have an abuse potential less than those in schedule 4, consisting of preparations containing limited amounts of certain narcotic drugs generally for antitussive and antidiarrheal purposes

Why is US legalese pharmacologically incorrect?

it refers to all/most illicit drugs as “narcotics”

T/F drug scheduling is based on science

FALSE, schedule for a given drug often has nothing to do with science/harm and is more of a political pawn

Substance Use Disorder

it becomes a disorder if it causes problems to social functioning (according to DSM), a social definition

T/F: people who try drugs usually do not go on to abuse them

TRUE

Pharmacokinetics

The life of a drug in the body; movement of drug to and from its site of action

How does a drug get in?

absorption and distribution + drug administration

How does a drug get out?

inactivated by liver + excreted from the intestines, kidneys, lungs, sweat glands, etc.

How/where a drug is administered impacts its absorption

-blood circulation at the site of administration, surface area of the absorbing surface, drug solubility, ionization

Oral Administration

advantage: easy

disadvantage: first pass metabolism, stomach acid, poor control

Example of a drug designed for first pass metabolism

vyvanse for kids which has an inactive prodrug which needs to get cleaved off in first pass metabolism for the drug to work, resulting in extended release

What are other non-invasive routs of administration that mostly avoid first pass metabolism?

nasal (bypasses BBB), sublingual, rectal, transdermal, inhalation

Injection Speeds

slowest to fastest: subcutaneous, intramuscular, intravenous

What are other injection forms in animals?

intraperitoneal, intracranial, intracerebroventricular

Why do routes of administration matter?

drug peak concentration and half-life vary by route of administration

What do drug users choose for route of admin?

any route that gives the highest peak concentration achieved rapidly to achieve a feeling of rush or euphoria

BBB

important to keep the brain environment as stable as possible, remember ink experiment for how this was discovered

Area Postrema

vomiting center, detects toxins in blood/CSF

What kinds of drug can easily diffuse across a membrane?

lipid soluble, neutral, small molecules

What kinds of drugs can not easily diffuse?

water soluble, charged, big

Degree of Ionization

when drugs are ionized, they become less lipid soluble, and therefore, the ionized form of drugs do not readily diffuse across cell membranes

Ion Trapping

differences in pH of different bodily fluids results in differences in the degree to which drugs are ionized in different fluid compartments, and thus can limit the ability of drugs to move between compartments, think of aspirin

T/F: all metabolites are inactive

FALSE, heroin is metabolized into morphine in the brain

What accounts for sex differences for alcohol absorption?

women have lower levels of alcohol dehydrogenase

What contributes to the feeling of hangover?

acetaldehyde

What do 50% of asians miss?

lack of aldehyde dehydrogenase gene

Drug Therapy for Alcoholics

disulfiram blocks aldehyde dehydrogenase which causes a severely negative reaction to alcohol

Pharmacodynamics

subfield of pharmacology dealing with the study of the biochemical effects of drugs and their mechanism of action

Receptor

the molecule a drug interacts with to initiate its biological effects

What kinds of interactions are drug receptor interactions?

weak non-covalent interactions

Are drug interactions reversible?

yes because they rapidly dissociate

T/F: drugs do not produce new or unique cellular responses

TRUE, they modify the rate of ongoing cellular events

Law of Mass Action

the more of a drug that binds, the more effect; when a drug binds to all action sites

ED50

dose that produces an effect in 50% of subjects

TD50

dose that produces a given toxic effect in 50% of subjects

LD50

dose that kills 50% of subjects

Therapeutic Index

TD50/ED50

Agonist

a drug that binds to a receptor and has a pharmacological/biological effect; has intrinsic activity

Intrinsic Activity

the effect of the agonist on the cell when it binds there, will cause a biological response

Potency

how much drug is needed to produce an effect

Efficacy

the maximum effect that can be produced by a drug

Why do some drugs have higher potency than others?

pharmacokinetic factors + the affinity of drugs for their receptors

Why do some drugs have higher efficacy than others?

they may act by different mechanisms and they may have more or less intrinsic activity at the same receptor

Antagonist

bind to receptors, have no intrinsic activity, their whole job is to block the activity of agonist

Competitive Antagonist

bind to the same receptor binding site, shifts dose-effect for agonist to the right

T/F: competitive antagonist effect cannot be overcome by agonist

FALSE, yes it can be overcome by sufficient dose of agonist, naloxone is a great example

Non-Competitive Antagonists

do not compete with agonist for binding site, shift dose curve to the right but also change its shape

T/F: non-competitive antagonism cannot be overcome by sufficient dose

TRUE, they make the receptors completely unavailable for drug action

What is an example of an irreversible antagonist? (note that most are reversible)

alpha-bungarotoxin

Full vs Partial Agonist

full agonists bind to receptors, have high intrinsic activity, whereas partial agonists have lower intrinsic activity

Inverse Agonist

has intrinsic activity, when a ligand binds to a receptor and reduces the receptor’s constitutive activity

Tolerance

drug effect getting smaller

Sensitization

drug effect gets bigger

T/F: drugs cannot show tolerance and sensitization at the same time

FALSE, chronic amphetamine use produces tolerance to euphoric and sympathomimetic effects while sensitizing psychosis-like effects and psychomotor effects

What does tolerance do to a dose-response curve?

shifts the curve to the right

Acute Tolerance

drug effect decreases rapidly within a single session (think alcohol)

Protracted Tolerance

drug effect decreases with repeated administration

Cross-Tolerance

drug effect decreases with repeated administration of another drug (alcohol and anesthesia)

What are the mechanisms of tolerance?

pharmacokinetic (enzyme induction) and pharmacodynamic (changes occuring to receptors and pathways)

How does conditioning contribute to overdoses?

drug tolerance can be specific to particular contexts-taking the same amount in a new place is lethal

Dependence

when tolerance has developed, so that ceasing drug use will result in withdrawal symptoms

What is interesting about withdrawal symptoms?

they are the opposite to the acute effects of the drug

What is the effect of sensitization on the dose effect curve?

curve shifts to the left

How can sensitization arise?

psychological factors/learning factors

Cross-Sensitization

taking one drug can make you more sensitive to another drug

What do the behavioral effects of drugs reflect?

complex interactions between the pharmacological actions, the state of the organism, and the environmental circumstances

Unconditioned

examining how drugs affect a wide range of naturally occurring behaviors (locomotion, rotarod, tail-flick test, elevated plus maze)

Conditioned

train animals to perform tasks to examine whether/how much animals are motivated to work for drugs (radial arm maze, morris water maze)

How are rats trained for drug discrimination?

teaching rats to press different buttons based on how they feel, trained to push one button for drug and one for saline

Positive Reinforcement

presentation increases the probability of preceding behavior

Negative Reinforcement

removal increases the probability of the preceding behavior

Punishment

decreases the probability of a behavior

Conditioned Reinforcer

a previously neutral stimulus that acquires its reinforcing properties from its association with a primary reinforcer

Conditioned Place Preference

place an animal on one side for drugs and one side for saline, see which side the animal chooses on a drug free day

advantages: simple, limited training, test in non-drug state

disadvantages: not measuring drug reward itself but rather the rewarding properties of secondary reinforcer and limited drug exposure

In FR schedules (fill in the blank)

typically get less responding at high drug doses (inverted U)

Progressive Ratio Schedules

exponential increase in number of responses, animals will press a button hundreds of time to get the drug

advantages: easy to compare drugs

disadvantages: one data point, only measures how much you “want” a drug while actively on the drug

What test is used for simulating someone coming home from rehab?

extinction-reinstatement test- train to administer with drug cue, extinguish response, present stimulus again to see if drug cue is reinstated (however more of a test of conditioned reinforcing effects)

What kind of SA test is best?

most addicts have intermittent access (so long term isn’t ideal), best is intermittent access (IntA) to have a higher reward on the drug and increases drug motivation to get high

Synapse

space between the pre and post synapses where the site of action for most psychoactive drugs occur

Steps in chemical synaptic transmission

synthesis, transport, storage, release, receptor binding, inactivation

What do NTs require to get into vesicles?

active transporters, vesicular transporters make use of the electrochemical gradient

What is required for release of a NT?

depolarization; shift in voltage

Steps in voltage-gated ion channel

channels open, ca2+ influx, bind to calcium calmodulin, phosphorylation of proteins, proteins move vesicles to release site, fusion of vesicle and exocytosis

How does the botulism toxin work?

cleaves proteins involved in vesicle fusion and neuromuscular junction which leads to muscle paralysisAu