ch 12: Cocaine + stimulants

cocaine is derived from ______, a shrub native to _____ → ____ produces 2/3 of the world supply.

• Erythroxylum coca

• the Andes Mountains

• COLOMBIA

forms of cocaine (3)

1. coca leaves: chewed → v. little abuse

2. powder cocaine (cocaine HCl) → oral, intranasal, IV, tropical

   1. typically cut w other powders ie. levamisole

3. freebase: the base (cocaine) is separated (freed) from the HCl to increase lipid solubility → crosses BBB more easily

   1. smoked → dangerously flammable

crack cocaine (2)

• base freed by combining with baking soda and drying

• smoked → more intense + rapid high than powder cocaine 

metabolism of cocaine (3)

• cytochrome P450 enzyme system in the liver

• excreted in the urine, sweat, saliva, and breast milk

• metabolites detectable in urine for 2-3 days after administration → up to 2 weeks in chronic users 

  • eg. benzolecgonine

routes of administration of cocaine in order of fastest absorption (3)

• smoking » injection > snorting > oral

• once absorbed, cocaine is rapidly broken down + excreted

  • subjective high lasts ~30mins 

most of cocaine’s actions are due to _________ by inhibiting _______ → increase ____ concentrations of ___ increases the rate of _____

• it’s ability to block reuptake of DA, NE, 5-HT

• their membrane transporters 

• synaptic concentrations

• transmitters

• transmission

cocaine’s behavioural effects + addictive potential is due to the inhibition of which NT and where

• inhibition of DA reuptake → increased dopamine in:

  • basal ganglia (movement)

  • PFC (planning, problem solving, decision making)

  • VTA and NAcc (reward + motivation)

how does cocaine stimulate mood + behaviour (6)

1. euphoria, elation, arousal, heightened energy + endurance

2. inflated self esteem + serl-absorption → overconfidence

3. enhanced physical strength

4. stereotypies: repetitive + compulsive bhvr 

5. focus more intently + feel mentally sharp but there is a negative effect on cognitive performance 

6. smoked or IV cocaine causes a rush

What are the acute physiological & psychological effects of cocaine (3)

• Sympathomimetic: ↑ HR, vasoconstriction, hypertension, hyperthermia

• Psych/behavioral: agitation, mania, paranoia, delirium

• High-dose risks: seizures, heart failure, stroke, intracranial hemorrhage

Which DA receptors mediate cocaine’s functional effects? (4)

• Receptor-selective tools: antagonists & knockout mice

• D₁: required for locomotor-stimulating effects;

  • D₁-KO mice don’t self-administer cocaine → key for reinforcement

• D₂/D₃: animals can self-administer; patterns differ from wild-type → contribute, but less critical than D₁

How does experimental cocaine use progress to use disorder? (4)

• Most who try don’t progress to misuse

• Typical initiation: snorting; some stop due to anxiety on first exposure

• Deterrents: cost/availability, legal risk, fear of addiction

• Progression: dose escalates and route shifts to crack, freebasing, or IV

What characterizes chronic use patterns and relapse risk? (3)

• Cocaine binges: repeated use over hours–days, little/no sleep → withdrawal afterward

• Risk factors: psychiatric comorbidity, stress, environmental cues, drug priming

• Incubation of craving: craving/relapse increase over time after withdrawal

What neurobiological changes occur with chronic cocaine use? (3)

• Reduced striatal dopaminergic activity on imaging.

• Down-regulation of DA system markers (e.g., DA synthesis capacity, VMAT2, D₂/D₃ receptor availability).

• Functional result: tolerance/anhedonia—more drug needed for the same effect, baseline reward tone drops.

How does chronic cocaine exposure change brain/behavior? What’s the difference between tolerance and sensitization? (4)

• Chronic use → neuroadaptations in DA system → behavioral change.

• Tolerance: ↓ response with repeated use (need more drug for same effect).

• Sensitization: ↑ response to same dose (especially “wanting”/incentive salience).

• Expression depends on pattern, context, time since last dose (tolerance → early; sensitization can grow over abstinence).

What are the serious health consequences of repeated/high-dose cocaine use? (4)

• Neuro/psych: stroke, seizures, panic attacks, paranoia/psychosis with delusions/hallucinations.

• Cardio/resp/renal/GI: arrhythmias, MI, lung injury, kidney injury, GI ischemia.

• ENT: septal perforation from chronic snorting.

• Pregnancy: fetal growth/neurobehavioral deficits.

What pharmacological strategies are being explored for cocaine use disorder (CUD)? (3)

• No FDA-approved meds yet.

• Replacement/agonist approaches: full/partial DA agonists or psychostimulants (e.g., amphetamine) as potential maintenance—mixed/limited efficacy.

• Vaccines: generate anti-cocaine antibodies to sequester drug in blood or enzyme vaccines to degrade cocaine (ethical/feasibility issues; no approvals).

Which behavioral/psychosocial treatments have evidence for CUD? (4)

• Psychosocial programs: individual/group/family counseling.

• CBT: cue identification, cognitive restructuring, coping/relapse-prevention skills.

• 12-step programs: Narcotics/Cocaine Anonymous—peer support/accountability.

• Contingency management: voucher/prize-based reinforcement for abstinence—strong evidence, often best when combined with CBT.

• Idea behind cocaine chemogenetics to blunt drug seeking?

Engineer ligand-gated ion channels that are opened by cocaine → drug-activated brake.

Where are channels expressed and what happens when cocaine is taken?

• Express selectively in reinforcement circuits (e.g., VTA→NAc, lateral habenula).

• Cocaine opens channel → hyperpolarizes/suppresses target neurons → ↓ DA surge, ↓ self-admin.

Why doesn’t it kill normal motivation?

Circuit-specific expression → natural rewards (food/sex) largely spared.

What receptor “backbones” are often used to build cocaine-gated channels and what’s the goal of the mutations? (2)

• Chimeras based on α7 nicotinic AChR / 5-HT3–like ligand-gated channels with binding-site mutations.

• Mutations shift agonist specificity so cocaine (not ACh) opens the channel → selective neuronal silencing during cocaine exposure.

Repeated long-access cocaine produces what DA-synapse changes? (5)

• Less DA made/stored → overall DA levels drop.

• Nerve terminal releases less DA when it fires.

• DAT isn’t blocked as well by cocaine anymore (transporter adapted).

• D₂ autoreceptors change (often less responsive).

• Result: the same dose gives a smaller DA rise → tolerance.

Contrast tolerance vs sensitization with intermittent exposure. (2)

• Tolerance: ↓ DA response to a given dose with continuous/high access.

• Sensitization: with intermittent/spaced dosing + abstinence → VTA LTP, ↑ burst firing, enhanced cue reactivity → ↑ “wanting” (craving) even if “liking” doesn’t grow.

What is incubation of craving and which process does it align with? (2)

• Time-dependent increase in cue-evoked craving during abstinence.

• Reflects sensitization-related plasticity (mesolimbic adaptations) rather than tolerance.

amphetamines (4)

• globally more popular than cocaine

• more potent + sustained effects

• administered by several routes

• easily + inexpensively synthesized

prevalence of use of amphetamines (4)

• 27 million ppl worldwide use amphetamine-type stimulants

• used to treat ADHD

• methamphetamine illegal in Canada

• prescription stimulants: Adderall, Vyvanse, Ritalin

forms of amphetamines → L vs R (3)

• amphetamine (benzedrine): mixture of left and right-handed molecules (chiral molecules)

• left-handed derivatives (levo-amphetamine): raises bp, opens nasal passages, causes headaches, no mood-elevating effects

• right-handed derivatives (dextro-amphetamine) → stronger effects in the brain, elevates mood, enhances energy ie. dexedrine 

methamphetamines (6)

• a methyl group is added to dextro-amphetamine (right-handed)

  • increases lipid solubulity + potency

  • better able to penetrate BBB

• chemicals to produce meth are readily available → corrosive, highly flammable, toxic

  • pseudoephedrine/ephedrine in OTC medications are used as the precursor 

  • sales restricted in US

structural differences between DA and amphetamines and ephedrine

DA → remove hydroxyls and add methyl = amphetamines add a methyl = methamphetamines

mechanism of action of amphetamines (4)

• increases postsynaptic lvls of DA, NE, 5-HT to a greater degree than cocaine by:

  • blocking reuptake by binding to transporter proteins

  • increasing release

  • at high doses, inhibiting MAO → preventing breakdown of catecholamines

high lvls of amphetamines lead to high lvls of catecholamines resulting in (3)

1. ↑NE: sympathomimetic effects

2. ↑5-HT: delusions + perceptual disturbances 

3. ↑DA: locomotor effects, psychotic side effects, reinforcing effects 

acute + adverse effects of amphetamines

• physiologically + psychologically similar effects to that of cocaine

  • slower onset of effects + longer duration

• side effects + withdrawal seen w amphetamines are qualitatively similar to those of cocaine 

medical + therapeutic uses of amphetamines (3)

• approved to treat ADHD

• narcolepsy: recurring + irresistible attacks of sleepiness during daytime hours, cataplexy, hypnagogic hallucinations, sleep paralysis

• short-term weight reduction: not anymore bc of high abuse potential

What are the major consequences of chronic amphetamine use? (9)

• Tolerance develops with repeated use.

• Skin & dental problems (“meth mouth,” sores).

• Cardiovascular: cardiac disease, hypertension; risk of sudden death.

• Cerebral hemorrhage (stroke risk).

• Renal (kidney) damage.

• Seizures.

• Amphetamine psychosis (paranoia, hallucinations).

• ↑ Psychiatric risk: mood/anxiety disorders, addiction.

• High doses—esp. methamphetamine: persistent/possibly irreversible neurotoxicity to dopaminergic & serotonergic terminals → long-term cognitive/affective changes.

What are the key administration routes and addiction risks for amphetamines vs methamphetamine? (4)

• Amphetamine: taken orally, IV, or subcutaneous (“skin popping”).

  • Oral absorption is slow; IV gives rapid, intense “high” → higher addiction risk.

• Methamphetamine is more potent; can be oral, snorted, IV, or smoked.

  • Crystal meth (“ice”) = methamphetamine HCl in smokeable crystalline form; highly addictive.

What patterns of use and pharmacokinetics characterize amphetamines? (3)

• Binges/runs: repeated injections every ~2 h for 3–6 days, little sleep/food.

• Metabolism: slow hepatic metabolism; metabolites excreted in urine.

• Long half-lives → a much longer-lasting high from a single dose vs cocaine.

How do amphetamines increase synaptic DA (± NE/5-HT)? (4)

• Enter presynaptic terminal (via DAT) and displace DA from vesicles by acting on VMAT2 → ↑ cytosolic DA.

• Trigger reverse transport through DAT → non-vesicular DA efflux into synapse.

• Kinase signaling (CaMKII/PKC) and Ca²⁺ facilitate DAT phosphorylation → promotes reverse transport.

• Net effect: large, rapid DA surge (and at high doses, NE/5-HT too).

neurobehavioural effects of amphetamines (3)

• cause heightened alertness, increased confidence, reduced fatigue, generalized sense of well-being

• reduced sleep time, esp. REM, permits sustained physical effort w/o rest or sleep

• can enhance athletic performance → banned in competition

how does withdrawal syndrome differ between opioids/alcohol and amphetamines? (3)

• withdrawal syndrome less sever than w opioids/alcohol

• negative reinforcement has less impact 

• women more likely to be dependent

where do meth uses show impairments? (5)

• multiple cognitive domains 

  • impulse control

  • verbal learning

  • working memory

  • social cognition

What major medical and neurobehavioral risks are linked to high-dose or chronic amphetamine/methamphetamine use? (4)

• Psychosis: meth use can precipitate persistent psychotic state (schizophrenia-like) that can last after abstinence.

• Neurotoxicity: damage/loss of DA neurons → long-term cognitive/affective deficits; ↑ risk of Parkinson’s disease.

• Cardiometabolic & GI: cardiovascular disease, stroke, GI distress; infections due to poor health/immune compromise.

• Other systemic: oral disease (“meth mouth”), male sexual dysfunction, premature aging, ↑ mortality.

3,4-methylenedioxymethamphetamine (MDMA) (4)

• synthetic amphetamine derivative

  • entactogen/empathogen → enhances social reward

• intermediate profile btw stimulants + hallucinogens

• clinical trials: MDMA-assisted psychotherapy for PTSD

what are the primary targets of MDMA and what are the bhvrl effects? (6)

• primary target: monoamine transporters

  • SERT reversed: massive 5-HT release

  • DAT reversed: moderate DA release

  • NET reversed: NE release

  • VMAT2: promotes vesicular monamine realse

• leads to mood elevation, empathy, arousal

acute subjective effects of MDMA (3)

• euphoria, empathy, emotional openness

• enhanced sensory perception → innervation of cortex

• increased sociability + energy 

acute physiological effects of MDMA(4)

• tachycardia, hyperthermia, jaw clenching

• risk of dehydration or hyponatremia 

• duration of effect ~3-6 hours

• onset: ~30-60 mins 

short-term neurochemical + bhvrl effect of MDMA(2)

• serotonin surge → mood elevation + sensory enhancement

• oxytocin release → social bonding

long-term neurochemical + bhvrl effect of MDMA (3)

• serotonin neurotoxicity → ↑ doses over long-term = cell death

• sleep, mood, memory impairments

• rebound depression (mid-week crash) → withdrawal effects → Tuesday suicide

ongoing MDMA investigations (3)

• MDMA-assisted therapy for PTSD (phase III trials)

• potential uses in depression + social anxiety 

• mechanistic studies on oxytocin + fear extinction 

caution with MDMA (2)

• neurotoxicity + serotonergic depletion remain concerns 

• controlled clinical environments essential for safe use 

cathinone (khat) + methcathinone (cat)

• khat:

  • leaves of a shrub in East Africa → used for centuries

  • one of the most popular stimulants worldwide

  • structurally + functionally similar to amphetamine + DA

• cat: synthetic variant → more potent

  • schedule III drugs

bath salts (4)

• The name derives from instances in which the drugs were disguised as bath salts.

• synthetic derivatives of cathinone

• can produce devastating physical + psychological effects

• mephedrone, methylone, MDPV → schedule III drugs