Drugs & Behavior Exam 2

Biological Characteristics of Users

Genetic, sex (F have more fat than H2O content, less dilution), weight, age (very young & very old get a greater effect from poorer enzyme systems)

Psychological Characteristics of Users

personality, sensation/adventure/experience seeking, disinhibition, boredom susceptibility, stress response dampening

Addictive Personality

hypothesis of a personality structure common to all with SUD, little evidence, impulsivity, aggression, thrill seeking, rebellious, gregarious, personal power, extroverted

Risk Factors for Drug Abuse

parental acceptance, poor school performance/attendance, alcohol before 13, emotional distress/conflict with parents, foster care

Protective Factors Against Young Drug Use

attachment to parent, parent supervision, school commitment, involvement in activities

Mithridates

prince in greece, mithridatism, antidote, tolerance

Types of Tolerance

Dispositional, Functional, Cross, Reverse

Dispositional Tolerance

metabolic, PK, NOT most common

Functional Tolerance

major form, site of action becomes less sensitive relative to PD, acute (tachyphylaxis) and protracted (extensive long term effect)

Cross Tolerance

tolerance to other drugs with similar effects, alcohol and anesthetics

Reverse Tolerance

sensitization - long term abstain → magnetized effect (coke & weed), PK left curve shift

Tolerance: Cell Adaptation

homeostasis reaching → brain in plastic, modulates neurotransmitter to get back to normal levels, down NT lvls and R lvls

Behavioral Tolerance

learned, conditioning, habituation, area affects drug effect, anticipation of reward triggers DA

Operant Conditioning

Reinforcement - increase behavior (pos add reward, neg take away bad)

Punishment - decrease behavior (pos add unpleasant thing, neg take away pleasant thing)

Animal Models of Reinforcement

• Self administration - extinction, reinstatement, drug discrimination, place preference

Reversibility of Tolerance

acute - quickly reverses

protracted - takes a while to reverse

learned/behavioral - difficult to reverse

Drug Development

long term, costly, often unsuccessful, animal testing min 7.25 years max 19.5 years

Naturally Occuring Stimulants

• Cocaine (Erythroxylum coco)

• Ephedrine (Ephedra) - shrub

• Cathinaone (khat) - shrub, metha

Synthetic Stimulants

• Amphetamines (Adderal, Dexedrine)

• Methamphetamine (crystal, ice)

• Pipradrol (1950 obesity, US banned 1970)

Cocaine Plant

Ethyroxylum Coca, coca leaf

History of Ethyroxylum Coca

• Incas 16th cent, provided energy (religious, med, work)

• 15th-16th Spanish paid with (did not USE)

• 1800s Europeans used, “naturalists”, exaggerated

• 1850s isolated & concentrated

• 1914 Harrison Narcotic Act limited amounts in products

• 20s-30s down cocaine up amphetamines

• 60s-80s down amphetamines up cocaine (healthier, apparently)

Cocaine vs. Coca Leaf

Cocaine - higher conc., faster, more potent, inhaled NOT chewed → faster PK

Cocaine is Treatment for:

Asthma, depression, indigestion, syphilis, addiction (morphine & alc), local anesthetic (procaine, novocaine)

Notable Cocaine Users

• Robert Louis Stevenson (Jekyll & Hyde)

• Thomas Edison

• Ulysses Grant (18th president)

• Sherlock Holmes

Amphetamines

synthetic stimulants, keep awake (WWII)

cold/sinus symptoms, obesity, narcolepsy, ADHD, heroin misuse

60s effects known, 70s cocaine believed to be better

Anti Drug Abuse Act (86 & 89)

specified penalties for cocaine sale & possession

limits on drug amounts

higher penalty on crack (2010 fair sentencing removed this) for racial targeting

1996 Comprehensive Methamphetamine Control Act

increased penalties for production and trafficking of meth

increased cocaine use

2006 Combat Methamphetamine Epidemic Act

regulate sale of products containing pseudoephedrine (that meth can be made of)

→ meth production returned to Mexico

Cocaine Sulfate/Smokable

plant soaked and mashed with kerosine, sulfuric acid, and solvents

resulting paste is dried, can be mixed with tobacco or made into cigs

Cocaine-HCl/Street Cocaine

powder, can snort or inject, cannot smoke
cocaine sulfate with added chemicals and dried again

Freebase Cocaine

cocaine HCl mixed with ether, can smoke. Heated to a vapor which is inhaled, warmed NOT burned

Crack Cocaine

mixed with baking soda & water → crystallized

heat to vapor, inhale vapor, same potency, makes a “crack”ling sound

Cocaine Pharmacokinetics

• ~10-15 mins to act if snorted or oral intake, seconds if smoked/inhaled

• lasts 20-80 minutes

• ~5 days for metabolism

  • benzoylecgonine

  • little bit norcocaine

Amphetamines Pharmacokinetics

• lasts 4-12 hours

• ~5 days for metabolism

  • benzoylecgonine

  • little bit norcocaine

Cocaine PNS actions (PD)

potent local anesthetic, powerful blood vessel constrictor, taste purity test (numbing)

Cocaine CNS Actions (PD)

powerful psychostimulant with reinforcement qualities, potentiates (increases) dopamine synaptic action of dopamine, norepinephrine, and serotonin (physiologically) and acutely - blocks reuptake

Amphetamine Function

blocks monoamine oxidase (enzymes that degrade dopamine & norepinphrine/monoamines)

blocks and reverses transporter reuptake of dopamine, norepinephrine, and serotonin

blocks transporter that fills vesicles with monoamines

Amphetamine Positive Effects

• sympathomimetic - mimics activation of sympathetic nervous system, stimulates

• inc heart rate, blood pressure, arousal, alertness, self-confidence, well being

• euphoria, prolonged intensive orgasm, promiscuity

• reinforcement of craving effects

Amphetamine Side Effects

appetite suppression, insomnia, irritability, involuntary motor activity, amythmias, snow lights

OD, death, seizures, depression, formication - bugs crawling under your skin

paranoid delusions - can be treated with …… (‘zine, da d2 antag)

Amphetamine Long Term High Dose Effects

paranoia, psychotic behavior, hallucinations, psychosis, interpersonal conflicts, bizarre or violent behavior

Amphetamine Drug Use Timeline

1. euphoric jump to mania

2. crash - mood drop

3. slow return to normal levels

higher dose → higher highs, lower lows, bigger crash

Stimulant Tolerance

tachyphylaxis - rapid/acute tolerance, within one session

repeated use → tolerance to euphoric feelings

intermittent use exacerbates withdrawal

Stimulant Withdrawal Symptoms

Dysphoria, depression, sleepiness, fatigue, bradycardia, profound craving

Sensitization

from animal studies, reverse tolerance, behavioral conditioning (anticipation) in humans

Stimulants Reward Pathway

• Pathway: dopamine in VTA → GABA/opioid peptides → nucleus accumbens: pos reinforce

• increase da at presynapt in VTA to NAc, chronic use → neg reinforce (brainstem, CRF, amygdala, norepinephrine)

Cocaine & Alcohol

• liver enzymes that metabolize both produce cocaethylene which acts like cocaine

• increases euphoric effects & dual dependency risk

• chronic use increases withdrawal, longer half life/more toxic

Cocaine & Heroin

• speedball, used by speed freaks

• more common in heroin addicts, enhances pleasurable cocaine effects

• common overdose cause - synergistic blood pressure and heart rate effects

Stimulant Misuse Treatment Factors

powerful reinforcing effects, high relapse tendency, additional psychiatric disorder & drug dependencies

Stimulant Misuse Treatment

need diagnosis of coexisting disorders, determination of prim or sec addiction, immediate and maintained abstinence

12 step recovery programs or psychopharmacology

unknown if abstinence reverses brain effects, some brain recovery (daR) after 14 months

Drugs for Stimulant Addiction Treatment

• desipramine - antidepressant

• bromocriptine - DA receptor blocker

• tyrosine - ups serotonin

• lithium - stabilizes mood

• topiramate - antiseizure med with anticraving effects

ADHD

inattention, impulsivity, hyperactivity, has reductions in reward pathways (striatum)

drug treatment → strattera - teen suicide, side effects (insomnia, tics, angry.irritable, loss of appetite)

ADHD Drugs

Concerta (slow release) and Ritalin - methylphenidate

Adderal - amphetamine

Strattera - atomoxetine (non-stim, norepinephrine reuptake inhibitor)

high misuse potentials, college misuse (gateway drugs?)

Tobacco History

from Americas, nicotainia tobacum, Spanish rediscovered and monopolized market

initially very expensive, 17th cent widespread & addictive properties seen

African natives traded land, livestock, and slaves for it → punishment by gov

Tobacco Medicinal Use Claims

pain treatment, skin disease, any injury

Nicotine Isolation

Pooselt & Reiman, german chemists. Named after french ambassador

Nicotine killing amount

60 mg (~30 mg has killed). 10-40mg per pack

Tobacco Processing

• Air: 4-8 weeks, cigar & burley, low sugar, high nicotine, light-sweet flavor, hung & dried

• Fire: 3-10 days, pipe, snuff, chewing, low sugar, smoky, high nicotine, hung over fire

• Flue: ~1 week, strung on sticks in flue, low heat no smoke, high sugar, med-high nicotine

• Sun: dry in sun, oriental tobacco, mediterranean areas, low sugar, low nicotine

Nicotine Inventions

1805 Chancel - self igniting matches

1883 Bonsack - rolling machines

Smoking Advertisement

highly advertised, Terry ‘64 → health risks, ‘99 cigs sued for racketeering, ‘06 warnings on labels & in ads, ‘17 ads about how smoking is bad for you

Why study smoking?

social and clinical significance, ubiquitous, addictiveness (one of the most addictive, debatable)

Age & Smoking

adolescent brain is more sensitive to the rewarding/reinforcing nicotine effects

Smoking Risk Factors

• Biopsychological - personality (hostile & aggressive)

• Psychologival - novelty seekers

• Social/Environmental - trying to fit in, soc/fam acceptance of nicotine use

Nicotine Administration (PK)

small lipid & water soluble molecule

inhale (10 sec), buccal (sublingual, ~15 minutes, smokeless. slowest), smoke (7-20 sec)

Treatments: gum (~30 mins), transdermal (5-12 hours), inhaler (nasal adsorption, 1 min)

Nicotine Pharmacokinetics

• first 3 puffs → saturated receptors, short lived psychoactive effects → repeated doses

• ~2hrs to metabolize, liver converts to cotanine, detectable for weeks

• tobacco contains MAOI (monoamine oxidase inhibitors)

• cigs - 0.5-2 mg nicotine, 0.1-0.4mg into blood

Nicotine Pharmacodynamics

nicotinic acetylcholine receptor agonist (nAChR)

cholinergic agonist, depolarizes (Ca and Na into cell)

nAChR throughout the NS, nerve-muscle connections, heart

MAOi → less dopamine breakdown

up dopamine in the nucleus accumbens (reward pathway), acts in VTA

higher affinity for brain nAChR’s, different config of polymer subunits

Nicotine Unpredictable Effects

due to effects on various neuro-effector and chemosensitive sites throughout the body (receptor stimulation)

vomiting, hormones, behavioral activity, tremors, alertness, learning & memory

Nicotine Poisoning

nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, headache, nausea, dizziness, disturbed senses, confusion, weakness, falling blood pressure (weird pulse), labored breathing

Nicotine Tolerance

occurs within a day, absence of nausea and dizziness with repeated intake

Nicotine Withdrawal

irritable, anger, anxiety, difficulty concentrating, restless, impatient, down heart rate, increased appetite/weight gain, can occur within the same day. One of the hardest addictions to break.

Nicotine Addiction/Withdrawal Factors

• Receptors: NAc/VTA DA release mess, glutamatergic & cholinergic synaptic transmission, GABAergic effects

• Environmental stimuli → strengthen dependence

• Reinforcement: pack a day → 200 reinforcements daily

  • dependence - neg reinforcement kicks in mult. times a day

Tobacco

• tar (chemical combo, many carcinogens) and nicotine

• CO formed from burning → CO binds to hemoglobin (suffocates cells)

• cancer from smoke - benzo[alpha]pyrene (mutagen), to BPDA (benzo[alpha]pyrene diolepoxide) which damages tumor suppressant genes

• more oral cancer than lung if not inhaled, women more likely to get cervical cancer

Coronary Obstructive Pulmonary Disease (COPD)

80-90% of smokers, down lung function

Emphysema - breakdown of alveoli sacks, suffocation

Smoking Diseases

• Coronary heart - atherosclerosis (blood vessels harden & narrow), thrombosis (clotting)

• Cardiovascular Lung - heart attack, atherosclerosis, kills more than lung cancer, from CO & nicotine

• from second hand smoke as well

Vaping vs. Smoking

Vaping: less carcinogenic, metal coil can flake off → lung damage, harmful flavorants & propylene glycol

Smoker Treatment

needs intrinsic (fear of getting sick) and extrinsic (nagging) to quit, very difficult

• Intervention - doctors AAAA (ask, advise, assist, arrange)

• Replacement - efficacy vs. effectiveness (patch/gum/lozenge)

• Medication, CBT (forever free), harm reduction (down intake)

• Vaccine - TA-NIC or NicVAX, ab for against BBB, smoking less pleasurable, nothing of this

Nicotine Treatment Medications

Bupropion (wellbutrin, zyban) - inhibit dopamine reuptake

Varenicline (chantix) - partial nicotine agonist, reduce craving

Caffeine History

1820 1st isolated Runge

From cacao pod, equator growing belt

Caffeine Amounts

chocolate (5-60mg, <25mg), kola nuts/coca cola (35 mg), tea (~30 mg, 10-90mg), coffee (150-200mg), pop (~50mg), headache pills

Methylxanthine

• caffeine

• theophyline

• theobromine

Caffeine use

highest Scandinavian (~414mg a day), ubiquitous use, cradle to the grave, 170mg/day US, highest dose by children, 2nd highest young adults

Caffeine Therapeutic Use

headache meds & help analgesics (excedrin), stimulate breathing & treat apnea in infants (dristan)

Caffeine PK

crosses BBB, peaks ~15-45 minutes, excreted in urine through the liver (~90%), 3-7 hour half life

Caffeine Metabolism Rate Factors

liver disease, age, pregnancy, contraceptive use, smoking

Caffeine Mechanism of Action

competitive antagonist of the adenosine receptor

adenosine receptors are metabotropic (g-protein coupled) and inhibatory.

cause redation, O2 to cell regulation, dilation of blood vessels, and asthma production when activated

causes increase in overall neural activation, stimulant like effects throughout the body, up epinephrine

Caffeine Neurotransmitter Effects

up acetylcholine, up dopamine, up norepinephrine, up 5-HT (serotonin? I think), down GABA

Caffeine Physiological Effects

• Peripheral: up metabolism, breathing, urination, blood pressure, vasodilation, sympathomimetic

• CNS: up activity, performance for simple tasks, shortens and delays sleep, postpones fatigue

Caffeine Large Dose Effects

headaches, jitteriness, tachycardia (fast heartbeat)

after ~1000mg → Caffeinism, diabetic state, high blood sugar, light headed, irregular heartbeat, tremors, breathless. can be caused by as little as 250mg/day

Caffeine Overdose

very rare, caffeine pills, 10g for adults, 100mg/kg children

Caffeine Chronic Use Effects

from above ~500 mg a day

insomnia, anxiety, depression, stomach ulcers, irregular heartbeat, up cholesterol (boiled up, Norway)

Caffeine Tolerance and Withdrawal

occurs rapidly, headaches, inability to focus, anti stimulant effects

mild withdrawal symptoms from >350mg a day (3-4 cups) or 1-2 cups, 12-24 hours to kick in, fatigue, sedation, headaches, irritability, nausea, lasts a week

Methylxanthines Therapeutic Effects

• caffeine (coffee) - cerebral & respiratory stim

• theophylline (tea) - coronary dilation

• theobromine (cocoa) - diuresis

Energy Drinks

• red bull - 111mg in 12 oz

• monster energy - 160mg in 16oz

• 5-hour energy - 200mg in 1.93 oz

• jolt cola - 280mg in 23.5 oz

• wired x505 - 505mg in 24 oz

• consume too fast. outlawed denmark, uruguay, turkey, australia; warnings canada & sweden, not FDA regulated, marketed towards teens and young adults

Energy Drinks & Alcohol

to party longer, stay awake, offset alcohol effects (counteract motor impairment & sedation)

Reduces PERCEPTION of headaches, weakness, and reduced motor coordination - no change in motor or rxn time

may result in greater motivation to drink, provides cross tolerance to cocaine, inc natural reward consumption (sugar & food), increased markers of neuronal activity in the nucleus accumbens

Anxiety

unrealistic, irrational fear or anxiety of disabling intensity, phobias

one of the most frequently observed mental disorders

general, social, PTSD, OCD

often with insomnia

Anxiety Treatments

alcohol, barbituates, Miltown (meprobamate), benzodiazepines

Barbiturates

small therapeutic window (dif btwn anxiolytic & sedative)

varied medical use that declined for safety (toxic & dependency liability)

Barbiturates Drugs

• Thiopental - 15mins, anesthetic

• Secobarbital - 1.5 hrs, sleep inducer

• Pentobarbital - 4 hrs, sedative & sleep inducer

• Phenobarbital - >6hrs, sedative or anticonvulsant

Miltown

meprobamate, ‘50s tranq in psych wards, high misuse potential

Benzodiazepines

librium (chlordiazepoxide, replaced miltown), valium (diazepam, more potent), serax (ozaepam), tranzene (clorazepate), Ativan (lorazepam), xanax (alprazolam, most common)

>3000 synth, ~3 dozen used

sedative, hypnotic, anticonvulsants, muscle relaxants, down aggression, down anxiety

works on 70-80% of patients

BZ vs. Barbiturates

BZ- more safe, less depression, larger therapeutic window, lesser suicide and abuse potentials, available antagonist, more specific, fewer side effects, works on the limbic system, less effective than anesthetics