Neurobiology of Addiction Exam 1

socially accepted uses of psychoactive drugs

1. religious ceremonies

2. social interactions

3. private pleasure

4. business

accepted uses change over time and vary between cultures

factors governing the extent of drug use

1. degree of social acceptance

2. social upheaval

3. legal controls (laws)

4. price

5. ease of availability

6. occupational factors (meperidine use by healthcare workers)

definitions of substance use and abuse

recreational use: occasional, controlled, or social use

drug abuse: causes physical or mental harm to the user

addiction: behavioral dependence

• a strong desire for a drug that results in damage to the individual and/or society

DSM-V definition of substance use disorder

cognitive, behavioral, and physiological symptoms indicating the individual continues using the substance despite significant problems

DSM-V criteria for substance use disorder

impaired control:

• taken in larger amount of longer time than intended

• persistent desire or unsuccessful al limiting use

• large amount of time getting substance or recovering

• craving** new in DSM V

social impairment:

• failure to perform major roles

• negative social consequences

• reduction in engagement in previously important activities

risky use:

• recurrent use in situations where it is physically hazardous

• use despite negative health consequences

pharmacological criteria:

• tolerance

• withdrawal

2+ symptoms = SUD (more symptoms → worse SUD)

stages and characteristics of addiction

acute reinforcement/social drug taking → escalating/compulsive use → dependence → withdrawal → protracted withdrawal → recovery or relapse

recreational users experience positive reinforcement

dependent users experience negative reinforcement

relapse is often spurred by drug cues or high stress

basics of intoxication vs withdrawal

intoxication: euphoria

withdrawal: dysphoria

psychiatric view of addiction

impulsive use: tension/arousal → impulsive acts → pleasure → guilt → tension/arousal

compulsive use: anxiety/stress → repetitive behaviors → relief (use) → obsessions → anxiety/stress

over time addiction progresses from impulsive to compulsive use

the addiction cycle

preoccupation/anticipation → binge intoxication → withdrawal →

the VTA → NAc projection is very important for maintaining the positive effects that contribute to this cycle

substance use population trends

• comorbidity with mood, anxiety, and personality disorders

• younger substance use = higher probability for lifelong dependence

• addiction has a multi-genetic and environmental component

• alcohol use has more overall addicts but less proportion of alcohol users are addicted

• often use multiple drugs (alcohol and nicotine)

• huge societal and medical cost

• most people who need treatment don’t get it

how can genes influence the risk for developing a substance use disorder

1. psychopharmacology (innate tolerance)

2. personality (impulsivity)

3. psychopathology (disorders)

4. physiology (metabolism)

classification of drugs with an abuse potential

schedule I: no officially recognized medical use and a high abuse potential

schedule II: officially recognized medical use and a high abuse potential

schedule III-V: decreasing abuse potential with an officially recognized medical use

what are drugs

any substance that is used to bring about a change in some existing process or state

however, they do not do new things in the body (mimic or block endogenous compounds)

origins of drugs

naturally-occurring, pure compounds, semi-synthetic, synthetic

paracellular passage of drugs

typical capillaries

passage between fenestra (small gaps) between cells

transcellular passage of cells

brain capillaries

going through a cell (tight junctions creating no gaps)

passive transport (across cell membranes or through aquaporins)

active transport

pinocytosis (cell drinking)

facilitated diffusion

factors affecting the passive transport of drugs

1. drug concentration gradient across the cell membrane

2. degree of ionization and drug polarity (P_m/b)

3. cell membrane surface area (much higher in small intestine than in the stomach)

4. binding to proteins (bound to albumin can’t get across)

dependence of drug absorption on pH and drug protonation

charged molecule (decreased absorption)

low pH (stomach) → organic acids are uncharged → higher absorption

high pH (small intestine) → organic amines are uncharged → higher absorption

common routes of administration

intravenous, subcutaneous, intramuscular, inhaled, oral

zero-order vs first-order elimination kinetics

zero-order: constant amount removed per unit time due to the enzymes being fully saturated

first-order: constant fraction removed per unit time (rate can be represented as a half-life)

pharmacodynamics principles

site and mechanism of drug action

site: where the drug acts to start the chain of events

mechanism: means by which the presence of a drug produces an alteration in function (often through receptors)

ED₅₀ and EC₅₀ curves

ED₅₀: required drug dose for half the maximal effect

EC₅₀: required drug concentration for half the maximal effect

show a logarithmic dose-response relationship that plateaus

the lower the EC₅₀ the higher the potency (does not measure the binding affinity)

therapeutic index (T.I.)

measure of the safety of a drug

TD₅₀/ED₅₀

higher = more safe

drug binding (affinity)

drug attraction to the receptor to form the DR complex

K_d (dissociation constant) = k_-1 (unbinding) /k₊₁ (binding): M units

• free drug concentration where half of binding sites are occupied

• lower the K_d the higher the binding affinity

• contributes to potency

drug efficacy

reflection of what the drug does after binding (DR → DR*)

efficacy E = beta (DR → DR*) / alpha (DR* → DR): unitless

• antagonists have no efficacy

• agonists have high efficacy

• inverse agonists have lower efficacy than baseline response

• contributes to potency

drug combination effects

1 + 1 = 2: additive

1 + 1 = 3: synergism

1 + 0 = 2: drug potentiation (modulation)

1 + 1 = 1: nothing (maxed out)

1 + 0 = 0: antagonism or negative modulation

competitive and non-competitive antagonism

competitive: reversible binding at a common binding site

• no change in maximal response (higher doses of the agonist can outcompete)

• increase in EC₅₀ (lower potency)

• rightward dose-response shift

non-competitive: reversible binding at a different site

• same EC₅₀ but decreased maximal response (efficacy)

  • some receptors are turned off

• both the agonist and antagonist can bind

allosteric modulators

bind to an allosteric site and affect receptor function

have no effect in the absence of an agonist

can increase or decrease the EC₅₀ but have no effect on the maximal efficacy

regulation of receptors

desensitization: the receptor becomes unresponsive to agonist

• closes and the agonist can no longer open it

down-regulation and internalization:

• receptor removed from the membrane and digested by lysosomes

advantages of animal models

1. control of the environment

2. control of genetics

3. assess behavior before vs. after administration (serve as own control)

4. selective manipulation of specific brain regions

5. gain information about brain regions, circuits, cells, and neurotransmitters

6. study different stages of the abuse cycle

limitations of animal models

1. anthropomorphizing (misattribution of human motivation)

2. doesn’t reproduce social factors of abuse

criteria to assess validity of animal models

face validity: does it appear to model the human condition

construct validity: does it measure what it is supposed to model

content validity: extent to which the model assesses the human condition (only certain aspects?)

predictive validity: can the model predict

voluntary drug consumption model and take-aways

two bottle choice: obtain ratio of preference for ethanol vs water/isocaloric sucrose

• to get animals to drink alcohol, sucrose fading used

• models escalation of amount of drinking

able to study the genetics of high alcohol vs low alcohol preference gene lines to help identify gene expression changes and treatments

predictive validity: acamprosate (AUD treatment) lowers consumption

conditioned place preference

two different unconditioned stimuli are repeatedly paired with two different environments

• test the amount of time spent in each environment

ketamine impairs CPP (prevents memory formation)

NMDA_r necessary to maintain CPP

conditioned place aversion: trigger withdrawal in a certain environment and measure time spent

tolerance and withdrawal

tolerance: adding a drug causes the body to adapt to restore homeostasis

this adaptation → withdrawal → craving → drug taking → restore homeostasis

depressant withdrawal: hyperexcitability

stimulant withdrawal: hyperinhibition

intracranial self-stimulation (ICSS)

ICSS threshold: the amount of current required to maintain the the ICSS

activation of neuronal circuits activated by traditional reinforcers

drugs of abuse decrease ICSS threshold (higher abuse liability the larger the decrease in threshold)

increased ICSS thresholds during withdrawal and high alcohol doses

issues with ICSS:

1. requirement for surgery for implantation

2. degree if ICSS depends on brain region

3. need for lots of training to determine and stabilize thresholds

4. effects of drugs on motor or performance capability

drug discrimination

tests if subjective effects are perceived by animals to be similar

determine doses/concentrations required to distinguish from saline

validity requires two hypotheses to be true:

• drug actions are perceived similarly by animals and humans

• discrimitive stimulus effects contribute to drug taking and relapse

the drug must produce a quick change in internal perceived state

can help in idenitfying receptor by using an antagonist or inverse agonist and seeing if it blocks discrimination

progressive ratio method

quantifies the reinforcing properties of drug abuse

how much work (higher ratio) to obtain a drug

reinforcement and punishment

positive punishment: add something unfavorable

negative punishment: remove something favorable

positive reinforcement: add something favorable

negative reinforcement: remove something unfavorable

animal models of the negative reinforcing effects of withdrawal

withdrawal effects are opposite to the drug acute effects and quantifiable

intermittent access (experiences withdrawal) escalates drug use

• animals comsume alcohol to avoid withdrawal

conditioned place aversion

sensitization to reinforcing effects of drugs

repeated INTERMITTENT administration of psychostimulants, opioids, and alcohol can cause a long-lasting enhancement of behavioral effects

• may be responsible for psychosis

self-administration and CPP used to study sensitization

rate of acquisition of psychostimulant self-administration is faster in animals that previously received noncontingent injection

cross-sensitization occurs within the same class of drugs

short-access for long-access drug escalation

more escalation of long-access than short-access

• may model controlled vs uncontrolled use

conditioned reinforcement paradigm

characterizes the incentive value imparted on previously neutral environmental stimuli after bring paired with drug self-administration

rat pressing lever presents cue and then administers drug

maintain lever presses in response to cued stimulus without drug administration

• also models craving

extinction with and without cues associated with IV drug self-administration

persistence of drug seeking behavior in absence of response-contingent drug deliveration

extinction via no longer rewarding responding with drug

measures the duration and number of extinction responding

• can also study reinstating responding with drug-cued stimuli

  • drug administration, drug cues, withdrawal symptoms

pharmacokinetic tolerance

metabolic tolerance due to the enhancement of drug metabolism usually by the liver

at the same concentration the same level of impairment is shown but a higher dose is required to achieve the same concentration

pharmacodynamic tolerance

functional tolerance, CNS tolerance, target-tissue tolerance

due to the decreased effect of the drug (neurotransmitter levels, affinities, and number of receptors, gene expression)

there is a lesser effect at the same concentration of the drug (right shift of the concentration response curve)

adaptive changes to offset the effects of drugs to restore homeostasis (more normal state in the continued presence of the drug)

pharmacokinetic tolerance to ethanol, barbiturates, and nicotine

ethanol: induction of CYP2E1 (not ADH)

barbiturates: induction of several cytochrome P450s

• massive tolerance causing the need of higher dosages

nicotine: increased brain (not liver) CYP2B1

all require chronic use for tolerance to occur

MDMA tolerance

MDMA inhibits its own metabolism by covalently binding (killing) the enzyme that metabolizes it

pharmacokinetic sensitization to MDMA lasting ~ 10 days

tolerance to cocaine

once daily use: sensitization to stimulating effect

continuous use: tolerance to stimulating effect

tolerance to the reinforcing effect occurs requiring higher doses to maintain self-administration

functional tolerance to alcohol

mice show less impairment at the same BAC

• this is even present in flies

context-specific tolerance can develop (form of learning) to ataxic effects

• this also applies in humans as cues can “prepare” the body for drug administration

functional cross tolerance

tolerance that develops to one drug causing tolerance to another drug even if it is a novel exposure

seen in drugs that produce similar pharmacological effects through similar mechanisms

cross-tolerance between cocaine and amphetamine but not morphine

acute functional tolerance

observed within the time from of a single exposure to the drug

lesser effect with the same concentration

dependence

physical dependence can only be demonstrated by eliciting withdrawal

cross-dependence

withdrawal caused by dependence to one drug can be relieved by another drug that has similar effects

• benzodiazepines relieve alcohol withdrawal