PSY 134 Midterm

Pharmacodynamics

– Alteration in the function or process of a tissue by the drug

relative to the physiologic condition that exists at the time of drug administration

– Lessening of pain

– Increase in euphoria

– Reduction in depression

Site of Action vs Mech of Action

– Part of the body (organ, tissue, cell, receptor/transporter protein) where a drug acts to initiate a chain of events leading to an effect

– Where a drug acts to produce an effect

vs.

– Means by which the presence of the drug produces an alteration in function at the site of action to produce a drug effect

– How a drug acts to produce an effect

Ehrlich’s Receptor theory

– A drug must interact by combining or binding with the macromolecular tissue element (receptor) at the site of action in order to initial a series of events that produce its biological effect

– Drugs can only produce their effects when they fit the receptor as a special key fits a well-designed lock

Ionic bonds

• holds drug to receptor

electrostatic attraction; transfer of electrons (- charged molecule binds to a + charged molecule & vice versa); rapid & relatively strong bond; can

occur across distances;

Covalent bonds

sharing a pair of electrons; very strong bond (20 times stronger than ionic bond); accounts for stability of most organic molecules

Hydrogen bond

type of ionic bond with hydrogen (+ charged); weak bond but if multiple hydrogen bonds are formed→high stability

Van der Waals forces

weak attractive forces between 2 neutral atoms; operate in close range; “final notches in key that open the door”

Dose

concentration depends on this and the time to get to and from the site of action.

• Factors of absorption, distribution, biotransformation, excretion

Law of Mass of Action

Drug + receptor <> drug-receptor complex →Effect
occupancy of receptors by drugs = free receptor concentration and drug concentration.

Kd

dissociation constant

• in equilibrium rate of combination = rate of dissociation

• lower Kd = higher affinity

radioligand binding assays

• radio tagged

Bmax

maximal binding=100% receptors are occupied ~ total number of receptors at target site

Affinity vs Potency DRC Functions

-Kd (slope); measures of binding ability of drug-receptor interaction.

-Dose needed to produce a particular effect of a given intensity. Low EC50 = high potency

Full inverse agonist

A drug that binds with full efficacy to a receptor but elicits a biological effect that is opposite to that produced by a traditional full agonist.

partial agonist

elicit a biological response upon binding but the magnitude of the response (efficacy) is reduced

• does not automatically mean affinity is also lower, they are independent of each other

competitive vs noncompetitive antagonists on DRC

-affect potency (shift curve right, same max) because their effect can be overcome. EC 50 increases

-Ki: concentration that results in 50% reduction in radioligand binding

vs

affect efficacy (lower max response) because their effect cannot be overcome.

5 major pharmacokinetic factors

contribute to the time-course of a drug’s effect

1. Routes of administration

2. Absorption and distribution

3. Binding

4. Inactivation

5. Excretion

Biological Barriers

cell membrane

• lipid bilayer> lipophilic drugs cross readily

• contains receptors

• contains transporters for hydrophilic drugs

capillaries/blood vessels

• higher blood flow and small molecules> rapidly crossing drugs

• intercellular clefts (pores) are large so hydrophilic solubility less of an issue

• lipophilic drugs cross readily

Biotransport

movement of a drug from one side of a biological barrier to the other without changing form

• passive diffusion: along concentration gradient

• facilitated diffusion: carrier protein/transporter that does not need atp

• active transport: transporter that requires atp

Major Routes of Drug Administration

Topical and Transdermal: fatty drugs (nicotine, certain opioids and steroids)

IV: by pass absorption; injected into blood stream

IN and SM: rapid absorption; lungs/ nasal membrane absorption > blood stream

IM & SC: slower, depends on the blood flow of the area

PO: different sites that affect the rate

weak acidic drugs are absorbed from the stomach due to the acidic environment and non ionization (undissociated).

• same with basic drugs in intestine but with a basic environment

Blood-Brain Barrier Features and Factors

-dense network of capillaries without pores

-capillaries are surrounded by a glial sheath provided by astrocytes

1. size of the drug molecule

2. fat solubility

3. ionization state

4. presence of transporter proteins for facilitated or active transport.

Choroid Plexus

drugs can pass into the brain by leaving and entering the CSF of this vascular organ

• located between blood capillary wall and ventricle wall

• contains active transporters for water-soluble drugs that cannot cross it readily

CYP microsomal enzymes

non synthetic rxn for lipid soluble compounds

• induction of the enzyme lessens drug effect (tolerance)

• inhibition of the enzyme increases amount of drug in system (sensitization)

  • Prozac inhibits, can lead to toxicity in ADTs, anti-asthma and anti psychotics

• competition between drugs on enzymes can lead to inhibitions (sensitization)

  • alc and valium

inhibited by grapefruit juice

Non-synthetic reactions

Phase I

• oxidation, reduction, and hydrolyiss

  • typically not eliminated, just modified

  • carried out by microsomal enzymes in liver, blood, brain

Synthetic Reactions

Phase II

• conjugations; coupling of the drug with natural molecule

• non microsomal enzymes (exception: glucuronidation)

• conjugated products: more water soluble for kidney excretion, usually inactive

First Order Kinetics

a rate of drug elimination

high conc.: high elimination

low conc.: slower elimination

logarithmic scale: straight line

half life: time required to eliminate ½ of the quanitity of drug that was in the system at the point when measurement began.

Zero Order Kinetics

rate of drug elimination

independent of the amount of drug and slows when carrier/enzyme mechanisms become saturated.

• alcohol

Time-Response Curve

• onset of action (latency): first administration and first measurable signs determine by absorption and distribution

• peak effect: max drug concentration, balance between absorption/distribution vs elimination. (can involve biotransformation to active form)

• duration of action: time of onset to the time when response is no longer measurable; affected by rate of elimination but also by re-absorption

Drug Depots

• drug binding at inactive sites where no biological effect is initiated (incl. plasma proteins like albumin, muscle, and fat).

• reducing its concentration at its sites of action & delaying effects

Pharmacokinetic Factor

Termination of Drug Action

– Excretion

– Biotransformation

– Tissue Redistribution

determine the duration of action of a drug

Biotransformation

Detoxification: change in the drugs that renders it less toxic

Metabolism: catabolism/break down of a drug to produce new molecules

Take place in intestine, plasma, kidney, brain & liver or be catalyzed reactions

Alcohol/drug Dependence

3 of the following < 12-month period:

1. Tolerance (↑ dose needed or ↓ effect)

2. Withdrawal (symptoms or use to avoid them)

3. Loss of control (uses more/longer than intended)

4. Failed attempts to quit/cut down

5. Time-consuming use (get/use/recover)

6. Activities reduced (social/work/recreation)

7. Continued use despite harm

Substance DSM Changes

• Combines abuse + dependence → “Substance-Related and Addictive Disorders”

• 11 criteria total (added craving)

• Adds cannabis & caffeine withdrawal (no caffeine use disorder)

• Includes behavioral addiction: gambling disorder

• Severity continuum scale:

  • 2–3 = mild

  • 4–5 = moderate

  • ≥6 = severe

temperament/personality traits

these contribute to abuse/addiction vulnerability

• disinhibition,

• negative affect,

• novelty

• sensation-seeking

co-morbid addiction risk

20-35% of individuals with drug dependence

• mood and anxiety disorders,

• antisocial personality,

• conduct disorder,

• psychotic disorders

developmental factors

age of initial drug use being a significant predictor of future drug abuse and addiction.

Heritability

proportion of observed variation in a particular trait that can be attributed to inherited versus environmental factors

in addiction: 40% for males and 60-70% for females.

• not 100% strongly suggests an interaction between genes and environment

• inconsistent with single-gene mendelian inheritance

Dependence View

Observed upon drug withdrawal and originally characterized as a physical syndrome.

redefined:
physiological—>both psychological and physical

Psychiatric View

Addiction has both aspects of impulse control disorders and compulsive disorders

impulse control element: driven by positive reinforcement

• before: tension, arousal

• after: pleasure/gratification/relief, may or may not be regret, self-reproach or guilt

compulsive element: anxitey or stress before, and relief from the stress (driven by negative reinforcement)

transition from positive>negative reinforcement

Psychodynamic View of Addiction

Developmental difficulties, emotional disturbances, structural (ego) factors, personality organization and the building of the Self

• critical elements:

  • discorded emotions, self-care

• contributory elements:

  • disordered self-esteem and relationships

modern self-medication hypothesis: individuals take drug as a “means to copy with painful or threatening emotions” or an attempt to medicate a dysregulated affective state

Social Psychological/Self-Regulation View of Addiction

Result of failed self-regulation; strength deficits, failure to establish standards or conflicts in standards, attentional failures and misdirected attempts to self regulate. A complete break-down in the ability to self-regulate

• Integrates well with current neurobiological views that addiction relates to dysregulated attention, information processing, planning, reasoning, behavioral inhibition.

  • ex: front cortex dysregulation in children as a predictor

Behavioral Sensitization

A progressive, long-lasting increase in a drug’s effect with repeated exposure; occurs with intermittent use (vs. tolerance with continuous use)

• is effect-specific (often psychomotor)

• increases over time/withdrawal

• can show cross-sensitization with drugs and stress.

Incentive Sensitization Theory of Addiction

“Wanting” ≠ “liking”; repeated drug use sensitizes the mesolimbic dopamine system.

• increasing incentive salience (wanting)

• drives craving and compulsive use even without increased pleasure

Opponent-Process theory

Drug use produces an initial “a process” (positive/pleasurable effect), which triggers a compensatory “b process” (opposing negative effect) to maintain homeostasis.

• repeated use: sensitizes “b process” and can mask “a process”

• individual increasingly takes drug to reduce the negative b process rather than gain pleasure

Neuorbiology of Addiction

neuroadaptations in transition from use/abuse to addiction

1. progressive down-regulation of the reward circuit

2. gradual recruitment of the anti-reward system

   • release of NE and coritcoptropin-relasing factor (CRF) and dynorphin

• limits reward

• mediates some of the aversive effects of stress

Allostatic Theory of addiction

with chronic drug use, there is a long-term shift in the brain’s reward set point (allostasis).

• The “b process becomes” larger,

• baseline from which both a and b processes operate shifts downward, creating a chronic negative state.

• drives compulsive use and dependence: taking drugs to fell normal (reduced reward and increased stress)
  include cocaine experimental evidence

ICSS experiment: homeostatic dysregulation

@ 10,20,40 infusions: lower ICSS after use bc cocaine is activating reward circuitry, this increases with more experience and withdrawal

@ 80 infusions: higher than baseline and higher ICSS during withdrawal

Addiction

(1)Compulsion to seek and take the drug

(2)Loss of control in limiting intake

(3)Emergence of negative emotional state during withdrawal


disease process of ____:

Preoccupation/anticipation→binge/intoxication→withdrawal/negative affect

Construct Validity

major criteria for animal model

-pathophysiological equivalence (common physiological dysfunction between model and condition)

Ex. Drinking alcohol by animal causes liver and brain damage

Predictive validity

major criteria for animal model

-ability to lead to accurate predications about the human phenomenon based on the response of the model

-ability of the model to identify pharmacological agents with potential therapeutic value

Ex. Alcohol intake by animals is reduced by acamprosate

Face validity

(least important) anima model criteria

-the model resembles the human condition

Ex. Animals self-administer drugs that are self-administered by humans

Reliability (validity)

(most important) animal model criteria

-stability and consistency with which the variable of interest can be measured; the phenomenon is readily reproduced under similar circumstances

Models of Binge/Intoxication

consumption of drugs in the non-dependent state; attempt to get at the neural processes mediating the positive rewarding and/or reinforcing properties of drugs

1) Direct drug self-administration (IV, PO, IG)

2) Lowering of brain stimulation reward thresholds (ICSS)

3) Conditioned place-preference

4) Operant runway

Operant Self Administration

Animal must perform a response to receive drug

• drug availability, drug unavailability or drug delivery can all be signaled by neutral stimuli. serve as a predictive/discriminative cues that guide future behavior in absence of the drug (conditioned reinforcement)

positive reinforcing: increase operant beahvior when presented/available

negative reinforcing: increases operant behavior when drug is removed. (increase during withdrawal)

Operant Learning Model Features

relative high face validity: both rats and humans are using self administered IV w stimulants and opioids

high predictive validity for abuse potential of novel compounds for humans

interpretations in self-administration:
increase: reliable patterns, high dose> animals back off, low dose> animals take more.

• animal will adjust behavior in predictable fashion

• can assay both appetitive (# of lever-presses/motivation) and consummatory (amount taken) aspects.

IV drug self administration cons (Operant learning)

Cons: technically complex and expensive, require extensive training and often IV surgery, can be difficult in mice, have high attrition rates, and may include confounds like food training. high subject attrition: issues like catheter failure and individual differences in drug sensitivity.

Interpretative limitations: complicated by reliance on learning, motivation, motor function, memory, and dose-response U curves.

low predictive validity regarding dopamine receptor antagonists: block self-administration but does not work for treating humans

Controls:

• Motor output control: inactive lever to check response specificity vs general arousal

• Motivation control: non-drug reward (e.g., sugar pellet, food pellet, sweetened milk)

• Learning control: train operant responding using a non-drug reinforcer

Second-order conditioning

Drug is paired with a neutral cue (light/tone). With repeated pairings, the cue becomes Pavlovianly reinforcing, so animals will press a lever for the cue alone (no drug needed).

Rationale: Measures indirect drug motivation (“craving”) via responding for drug-associated cues rather than the drug itself.

progressive-ratio reinforcement

The number of responses required for each drug reward increases step-by-step until the animal stops responding.

Break point: The last completed ratio, indicating the maximum effort the animal will expend for the drug.

Rationale: Assesses motivational strength of animal strain / willingness to work for drug (higher break point = higher motivation).

Oral Self-administration

confounds: A non-operant method of drug intake where animals voluntarily consume a drug by drinking from a bottle or sipper tube, rather than performing a learned response (e.g., lever pressing).

• Commonly uses 2-bottle or multiple-bottle choice paradigms to measure intake and preference.

controls:

DID model

Limited Access Model

2-4 hr presentation of 20% alc at 3 hrs into dark cycle, can be multiple bottles

• engenders high levels of alc intake

• predictive validity under investigation (possibly good for pharmacotherapeutics but not genetics)

employed as a model of binge drinking

• brings blood alcohol concentration (BAC) to 0.08 gram percent or above.

High face validity: happy hour

ICSS studies

Operant Procedure

• Directly activates reward/motivation circuits involved in natural and drug reinforcement.

Measures: Stimulation threshold (frequency/intensity needed for responding)

Drug Effects: Drugs of abuse (except THC): ↓ ICSS threshold → enhanced reward function (less stimulation needed)

Monoamine antagonists: ↑ ICSS threshold → reduced reward function (more stimulation needed)

High predictive validity for abuse potential and some therapeutics

Shares confounds of operant tasks (refer to flashcard)

Drug discrimination studies

Behavioral procedure used to measure a drug’s interoceptive (subjective) effects by seeing how similar they feel to a known training drug. typically uses food reinforcing training

Rationale: Since addictive drugs are taken for their subjective effects, drugs that “feel like” known drugs of abuse are more likely to have abuse potential

• (high predictive validity for humans).

1. saline vs drug discrimination

2. administer novel drug, see whether it categorizes it as saline or drug.

• compares subjective effects across different groups

  • gender, genes, stress levels, withdrawal stages

Place-conditioning model

non-operant procedure

• biased (requires sal-sal control) vs unbiased enviornments (does not require sal-sal control)

advantages: high predictive validity, measures both ± motivational properities, no impact on motor effects of drug behavior (tested in drug-free state, however withdrawal may impact this), simple and time-efficient design.

disadvantages: animal is not taking the drug (lessens face validity), animals needs to be able to tell the compartments apart.

Ettenberg Runway Model

An operant drug self-administration task where animals must run down a long alley to a goal box to receive drug infusion. It measures motivation in a drug-free state, including:

• Latency to start/leave goal box

• Time to traverse alley

• Retreat frequency (approach–avoidance conflict)

  • cocaine can produce progressive increases in retreat behavior.

predictive validity for drugs both rewarding and aversive effects

Limitations: semi-contingent drug delivery, requires specialized equipment, catheter failure risk, high variability between animals, and need for large sample sizes

Aversive Properties of Drug Withdrawal

what these models can assay

• Operant Self-administration: perform operant activity more

  • Drug Discrimination: choose the drug

  • ICSS: more stimulation

• Place Conditioning: go to the area where no drug was associated

Extinction and Reinstatement Procedures

Craving Model

1. Drug-seeking behavior is reduced by replacing drug with saline or removing it, so responding declines with repeated testing.

2. Drug-seeking returns when animals are exposed to:

• Drug (priming dose)

• Drug-associated cues

• Stress

→ Models relapse in humans

applicable to both operant and non-operant models

validity of extinction: low face validity (humans don’t undergo formal extinction training).

Abstinence Models

After prolonged drug exposure, animals undergo extended withdrawal (>1 week)

Even after acute withdrawal ends, they show:

• Negative affect (e.g., anxiety-like state

• Increased drug intake (IV or oral)

• Heightened sensitivity to drug cues

→ Models protracted withdrawal and relapse vulnerability

Higher face validity than extinction models (closer to human addiction)

Long-access (Protracted periods) Model

in IV self-administration models

1. Establish baseline intake under limited access (1–2 hrs/day ~1 week)

2. Then give a subgroup long access (4–12 hrs/day)

• greater intake, increased drug-motivation, reduced sensitivity to aversive effects

pros: models transition to compulsive use (loss of control), good face validity for addiction (escalation, motivation changes)

cons: technically difficult, high variability across animals, time-consuming and costly.

Contingency

Contingent: Drug delivery depends on the animal’s behavior

• → e.g., lever press → drug (Operant)

Non-contingent: Drug is given independent of behavior

• → e.g., experimenter injection, timed infusion (Place conditioning, Oral)

Semi-contingent: Drug delivery is partially dependent on behavior but constrained

• → e.g., animal performs action, but delivery is limited/delayed/not fully under control (ettenberg)

Incubation of Craving Model

protracted abstinence from long-access drug self-administration

• time dependent increase in cue-induced drug-seeking

• sensitization “incubation” of craving. drug-associated cues get stronger over time, even without drug exposure.

Drug-Dependent behavior

noncontingent

rationale:

• Model drug dependence by inducing a chronic drug state and then assessing how it alters motivation for drug

• Tests whether dependence leads to increased drug-seeking and intake

determined by:

• Establish baseline intake → induce dependence via Non-contingent drug administration (e.g., alcohol vapor, morphine pellet, repeated injections)

• OR long-access operant self-administration (weeks)

Retest under operant procedures or place-conditioning procedures.

Non-Operant Procedures

• Most Oral Procedures

  • DID, 2 bottles, multiple bottle choice

• Place Conditioning

Tolerance

lessening of a drug effect (either reduced potency, efficacy or both) from the repeated administration of a drug

• requires higher dose for a given effect

• apparent by a shift downwards or to the right in a DRC

• to specific drug effects not all effects

• doesn’t last forever, and it depends on the drug effect.

Sensitization

heightening of a drug effect (either increased potency, efficacy or both) from the repeated administration of a drug (i.e., reverse tolerance)

• lower dose to achieve a given effect.

• shift upwards or to the left in a DRC

• develops to a drug effect NOT to all effects

• persistence of sensitization to a drug effect varies depending on the effect but tend to be quite long-lasting

• increase with time

Acute Tolerance

Occurs during the first drug exposure

Drug effect decreases within the same session, especially on the descending limb of the dose-time curve

• peak intoxication happens before peak blood levels

Cross-tolerance

Repeated administration of a drug diminishes the effects of another drug

Ex. Repeated oxycodone → tolerance to the analgesic effects of oxycodone, morphine, codeine etc.

-Suggests that the drugs are exerting their effects by a common mechanism

Cross-sensitization

Prior treatment with 1 drug can render an individual more sensitive to the acute effects of another drug (implies common mechanisms; e.g., prior alcohol→increase sensitivity to cocaine, amphetamine and morphine locomotion)

Major Mechanisms of Drug Tolerance Development

1. Pharmacokinetic/metabolic tolerance

   • increase in matabolisim rate of the drug/ enzyme induction,

2. Pharmacodynamic/physiological/cellular tolerance

   • homeostasis> feedback loops, receptor density/intracelluar coupling, changes in nt release

     1. agonists(reduce activation)/antagonists (increase activation)

3. Behavioral tolerance

Mechanisms of Drug Sensitization Development

1. pharmacokinetic/metabolic sensitization

   • inhibition of metabolic enzymes, all drug effects are effected
     Agonist effect is larger, antagonist effect is smaller

2. Pharmacodynamic/physiological/cellular sensitization

   • additional circuits, receptor density/intracellular coupling, nt release

   • agonists (increase activation)/antagonists (reduce activation)

conditioned tolerance

The compensatory mechanisms against a drug effect become conditioned to external stimuli

• Can be extremely long-lasting and persist well beyond physical withdrawal

• Can only be lessened by extinction learning

• Hot Plate Test (behavioral)

  • New environment → drug works better

    Familiar drug-paired environment → drug works worse (hyperaglesia)

OD risk: environmental cues which reduce drug effect. in a new environment those cues are absent, no compensatory response, leading to a stronger effect and overdose risk.

Conditioned sensitization

The sensitized response in drug experienced individuals is greater

when the drug is administered in a familiar environment.

• Can reflect a conditioned increase in drug efficacy, drug potency or both.
  
  OD risk: drug associated cues can trigger enhanced responses.

Pharmacokinetic tolerance/sensitization

when a fixed drug dose is administered daily and the drug levels change along with a behavior change in the blood/brain what kind of tolerance/sensitization pharmaco property is this?

Detoxification

first step in addiction recovery, but does not address psychological, social or behavioral problems

unpleasant/dysphoric> serve as negative reinforcers and can induce relapse.
fatal in sedative-hypnotic drugs (seizures) or unpleasant

• for alc, benzodiazepine, barbiturate withdrawal? administer anti-convulsant or GABAergic drugs to minimize over-excitability

• opioid withdrawal? administer anti-diarrheal/nausea meds

Behavioral Therapy

general procedure

Engaging, provide incentives, modify attitudes and behaviors and increase life skills to cope with stress and craving

Substitution/replacement therapies

gradually decreases dose of abuse substance and pharmacologically similar but longer-acting drug.

• lessen withdrawal/detoxification severity

• progressively reverses neuroadaptations

• lessens cravings bc targets are still stimulated

• may produce cross-tolerance to reduce subjective effects if relapse occur
  

for opioids (2) (pharmacologically similar)

• methadone and LAAM (more effective)

• agonists at the MOR (mu opioid receptor)

• less efficacy but longer half-life’s

for nicotine (3) (lower dose)

• patches, gums, lozenges

Partial agonist Therapy

Have some level of receptor stimulation (reduce propensity for withdrawal, craving etc)

• competitive drug

opioids: Buprenorphine (Subutex) for heroin

smoking: varenicline (Chantix)

loophole: if you take enough of the abusive drug it could outcompete the therapy drug

Antagonist Therapy

Administer an ______ of the receptor activated by the drug of abuse and block it’s effects

• (e.g., naltrexone or naloxone for opioid addiction)

• competitive drug

loophole: if you take enough of the abusive drug it could outcompete the therapy drug

Dopamine Reuptake Inhibitors

Reduces stress-induced cravings. Falls under:

“Reward Enhancing” Therapy

• elevates dopamine transmission so the dopaminergic impact of the drug is less detectable

• mitigates stress-induced drug-taking (smoking) and relapse

  • Zyban/Wellbutrin (NDRI) also for nicotine addiction

Opioid Addictions

low compliance for administering competitive opioid antagonists

naloxone and acamprosate

for treating alcoholism and perhaps addiction to other non-opioid drugs of abuse

Antabuse

“Aversion Therapy” drug for alcohol
aversive properties of a drug of abuse have low compliance

• causes hang over and can be fatal, cannot consume alc for at least 2 weeks after taking Antabuse.

• works only in highly motivated people

Vaccination Therapy

problem: It relies on the body producing enough antibodies, but there is high individual variability in immune response,