Lecture 7 Cocaine and Amphetamines

what differentiates stimulants like cocaine and amphetamine from nicotine and caffeine? (1)

they are much more potent

characteristics of a stimulant (1)

stimulates nervous system; increases heart rate, breathing rate; increased alertness; reduced sleepiness

cocaine and amph route of administration (2)

ingested, injected, snorted, smoked; (cocaine can also be applied topically)

cocaine and amph duration of effect (2)

cocaine 1-3 hours (powder), 5-30 minutes (crack); amph 2-12 hours (depending on type)

cocaine and amph neurotransmitter directly affected (2)

dopamine (also norepinephrine and serotonin)

cocaine and amph tolerance (2)

moderate, with some reverse tolerance (higher for amph)

cocaine and amph physical dependence

moderate (higher for amph)

cocaine and amph psychological dependence

high

cocaine and amph withdrawal symptoms

depression, anxiety, drug craving

cocaine and amph schedule

1 (a couple of medical uses for certain cocaine and derivitaves of amph e.g., adderal)

the cocaine experience (4)

rush will be faster than last shorter if snorted vs ingested orally; tastes a bit like chlorine, powder will numb the face; smoking even faster, less numbing and taste; intense, narrow vision, ears ringing. stimulating.

where is cocaine from? (6)

coca leaves which grow in the Andes in South America

how were coca leaves used in Inca cultures? (6)

chewed (similar to chewing tobacco, lasts a while); results in very slow absorption. also drinked in tea.

three major countries where cocaine is cultivated (7)

columbia, peru, bolivia.

freud and cocaine (8)

at first saw it as a cure-all, but eventually oppsed its use due its addictive potential.

historicial medicinal use of cocaine (9)

anesthetic; patented tonics and elixirs; coca-cola; used as a treatment for depression and morphine dependence

when did cocaine stop being available over the counter in the states? (10)

in 1916 due to the Harrison Narcotic Act

when was Cocaine criminalized in Canada? (10)

1923

when did cocaine’s popularity rise? (11)

in the 70s and 80s; snorting or IV injection; rock and roll/glamous lifestyle; crack cocaine was considered more “lowly” and “poor”.

when did crack cocaine start to appear in the US and Canada? (11)

1984

if you ask canadians 15 and older what drugs they have ever experimented with, what are the top three? (12)

alcohol (78%), cannabis (14.8%), cocaine (~2.5%)

forms of cocaine (17)

coca leaf, coca paste, cocaine (cocaine hydrochloride), crack

how and why is cocaine converted into crack? (17)

freebase cocaine is dissolved in baking soda as freebase cocaine cannot be smoked as it breaks down at high temps

smoking crack vs snorting cocaine power (18)

crack has a higher bioavailability (90% vs 75%); faster onset (1-2s vs 10-30s); and shorter duration (2-15m vs 2h)

soluability of cocaine (21)

water and fat soluable resulting in quick distribution through body, BBB, and can pass through the placenta.

cocaine metabolites (22)

broken down into various metabolites; one is an active metabolite

cocaine half life (22)

0.5-1.5 hours; major metabolites have half lives of around 8 hours

cocaine and alcohol (23)

produces cocaethylene, active metabolite with greater potency and longer half life than cocaine

cocaine elimination (24)

mainly in the urine, but also sweat, saliva and breast milk.

how long can you detect cocaine in urine? (24)

for 2-3 days after administration, and up to 2 weeks and chronic users

Most importan DA pathway for reinforcement of drugs (26)

mesolimbic aka mesolimbocortical pathway; goes from deep midbrain neurons to various areas of the brain including pre-frontal cortex

which neurotransmitter does cocaine replace? (27)

Cocaine does NOT resemble any neurotransmitter

Cocaine mechanism of action at lower/normal dosages (27)

blocks DA transporters, which takes dopamine back up into the presynaptic cell from the synaptic cleft to be reused. This results in more free dopamine in the synaptic cleft. Similar effect on serotonine and norepinephrine.

Cocaine mechanism of action of higher dosages (28)

inhibits voltage-gated Na+ channel in axons, which blocks nerve conduction, acting as a local anesthetic.

Drugs that use cocaine’s anesthetic effects (28)

procaine (novacain) and lidocaine (xylocaine) were developed from cocaine

how do we know that cocaine works on dopamine transporters? (29)

GMO mice with dopamine transporters which can’t be blocked by cocaine will not self-administer the drug.

Behavioural vs cellular responses to cocaine in mice (31)

low cocaine responders had greater baseline DAT expression (more transporter); same variation might be present in humans

Which DA recpetor is important for cocaine? (32)

D1 receptor; knockout mice don’t self-administer

PET imaging of cocaine users vs control (33)

cocaine users will have lower D2 availability (either fewer or altered receptors), and occupancy will not increases as much after amphetamine as the control.

sympathomimetic drugs (35)

produces symptoms of sympatheic nercous system activation

symptoms of an activated (or seemingly activated) sympathetic nervous system (35)

constricted blood vessels, dilated pupils; euphorial, exhilaration; alertness; self-esteem; etc

effects of higher doses of cocaine in humans (36)

bizarre, erratic, violent behaviour; restlessness, irritability, anxiety, panic, paranoia; tremors, muscles twitches; fatality from seizures, stroke, heart failure, etc; can induce a psychotic break

effects of higher doses of cocaine in animals (36)

repetitive, stereotypical behaviours,

formication (37)

an unusual side effect of cocaine use called delusional parasitosis, a delusion that insects are crawling in and under one’s skin

Long terms effects / considerations of cocaine use (38)

cardiovascukat issues, seizures, sexual dysfunction (increase interest, decrease performance), risk to nasal cavities if snorting; risk to lungs if smoking; risk of injury or infections from cracked pipes if smoking

what proprotion of individuals who try cocaine progress to misuse? (40)

most don’t progress to misuse.

characteristics of cocaine users progressing to misuse (40)

use escalates, binges become more common, route of admin may switch from snorting to crack or IV injection

Acute Tolerance of cocaine (41)

can happen within a single session/binge; half hour half life; 2nd bump won’t feel as good

withdrawal symptoms of cocaine (41)

physical symptoms are not life-threatening; psychological symptoms include changes in mood, irritability, tired, groggy, compelling drug craving; drug craving lasts the longest, perhaps years.

tolerance and sensitization from chronic cocaine use (42)

both tolerance and sensitization are seen specific to certain effects of the drug; sensitization tends to last longer than the tolerance

toleration from chronic cocaine use (42)

e.g., locomotor-stimulating effects, less activity

sensitization from chronic cocaine use (42)

e.g., stereotyped behaviours (repeated washing in animals)

chronic cocaine use and cognition (46)

cocaine dependence can cause numerous cognitive deficits, especially in the prefrontal cortex (e.g., impulse control, issues with working memory, decision making, etc); MRI studies show adnormalites in the PFC, ACC, insula, dorsal striatum, amygdala, thalamus

physical consequences of regular high-dose cocaine use (47)

stroke, seizures; organ systems (e.g., cardiovascular); perforation of the nasal septum (if cocaine is snorted); developmental and cognitive usses for children after pregnancy.

effects of highest-dose cocaine use (47)

panic attacks and paranoid psychosis; may also trigger psychological disorder or result in more permanent psychosis (rare)

Amphetamine slang (48)

bennies, uppers, dixies, “black beauties”, diet pills

Methanphetamine slang (48)

meth, speed, crystal, crank, ice (smokable form)

Methanphetamine vs cocaine (49)

overall stronger: more potent, longer lasting, 12h half life, increases dopamine release AND blocks dopamine re-uptake; meth has limited medical use for ADHD, narcolepsy and weight-loss.

cocaine and anphetamine see-saw effect (50)

1900s miracle drug until 1920 where is it banned in OTC; amphetamines rise in popularity until concerns grow about abuse; 70s-80s: cocaine considered glamourous and safe, except crack; 1990s-now: amphetamine use is rising, due to “smart pills” and methamphetamine use

amphetamine vs meth vs adderal (51)

amph will give you a high for 3-6 hours, stimulating (heart rate, sociality, talkative, etc), unpleasant to come down. Meth: alert, confident, energized, at least 10h, worse to come down off of (tired, depressed, etc). adderal: not much of a high for those with ADHD, help with alertness and focus, but off-label use will get a bit of a rush when using it but less likely to feel more focused.

Molecular structire of amph (53)

synthetic, structurally related to DA, more potent.

molecular structure of meth (53)

same family as amph; addiitonal methyl group allows it to cross the BBB more readily.

molecular forms of amph (54)

L-amphetamine, which is less potent (left; levoamphetamine; e.g., Benzedrine) and D-amphetamine, which is more potent (right; dextroamphetamine; e.g., Dexedrine)

Adderal contents (54)

contains a 3:1 misture of d-amph and l-amph; immediate and delated release formulas exist.

Amphetamine in the 1940s (58)

soldiers in WWII used amphetamines (“go pills” or “pep pills”) to fight fatigue

amphetamine in the 1960s (58)

most street amphetamines came from prescriptions; abused by athletes, students, truck drivers.

what is a speed ball? (58)

mix of amphetamine with heroine

Methylphenidate (Ritalin, Concerta; 59)

make in 1944 to treat chronic fatigue and depression; approved for use in ADHD by FDA in 1955; stimulant drug with slightly different mechanism of action than amphetamine

Adderall vs Ritalin (59)

Adderall has the same mechanism of action as amphetamine whereas Methylphenidate (Ritalin) does not.

Adderall misuse (60)

as many as 30% of US stuydents are abusing Adderall; esp in college students and youth

amphetamine mechanism of action (69)

direct agonist of the catecholaminergic systems; blocks the reuptake of DA and NE; Enters nerve terminal by DAT to stimulate release; alters DAT to act in reverse (release DA instead of reuptake); come down is bad due to dopamine depletion (increases rate not total supply)

Amphetamine binges and crashes (72)

speed runs; withdrawal symptoms: depression, anxiety, changes in appetite, sleeping disturbances, craving; crash puts you way below baseline, and includes intense cravings. No life-threatening physical withdrawal symptoms.

physical effects of long-term meth use

extreme weight loss (due to appetite suppressance); “meth mouth” (esp from dry mouth from smoking); Formication, skin sores; increased risk of infectious diseases (ie. HIV or Hep B and C); premature aging

Adverse effects of chronic use ( 74)

chronic, high-dose abuse can result in possible psychotic reactions (with a potential transition to a persistent psychotic state, similar to paranoid schizophrenia); cognitive tasks; parkinson’s, cardiovascular disease, GI distress, sexual dysfunction, oral diseases.

neurotoxicity (75)

death or damage to Da neurons shown in animals after 3 doses of meth; may be due to oxidative stress, excitotoxicity, neuroinflammation, mitochondria dysfuntion, etc.