lecture 10 - Psychomotor Stimulants: Cocaine & Amphetamine

molecular structure of cocaine & amphetamines

has similar structure to dopamine & norepinephrine

mesostriatal dopamine structure

• basal gangla (striatum)

^^^^^

• substantia nigra (SN)

• → voluntary movements

mesolimbic dopamine system

• nucleus accumbens (NAc)

^^^^^

• ventral tegmental area (VTA)

• → anticipation, motivation/seeking

mesocortical dopamine system

• prefrontal cortex (PFC)

^^^^^

• ventral tegmental area (VTA)

• → executive function (EF): cognition, attention, memory

psychomotor stimulants: effect on dopaminergic systems

• psychomotor stimulants like cocaine increase DA activity across the brain, affecting multiple dopamine-run systems

  • mesostriatal system: restlessness, hyperactivity, stereotypy & repetitive behavior @ higher doses

  • mesocortical systems: euphoria, cortical arousal, focused attention 

    • @ higher doses → hallucinations & psychotic systems 

psychomotor stimulants: effects on noredrenergic (NE) systems

• psychomotor stimulants will also increase synaptic NE activity → esp. @ higher doses

• PNS: acts as a sympathomimetic

  • increased HR/BP, increased respiration, suppressed appetite, etc.

• CNS: reticular activating systems (RAs) → become overactive, esp. through locus coeruleus release of NE 

cocaine: products of the 19th century

• toothache drops → numbs soft tissue

• “coca” wine

• “coca” - cola

cocaine is a DEA Schedule II psychostimulant

leaves, powder, crack, pre-cursor

cocaine PharmK: Administration & Distribution 

• coca leaf chewing

  • slow but lasts a long time

  • need a good amount

• intranasal: snorting cocaine HCl

  • fast and lasts a little bit less than orally

  • least amount of dose needed

• intravenous: cocaine HCl

  • fast but doesn’t last long

  • also need a good amount

• smoking: coca-paste, free base, crack

  • fastest but high barely lasts

  • need a huge amount 

cocaine PharmK: metabolism

• metabolism: fast, near complete metabolism by liver & plasma enzymes

  • half-life = 45 minutes

  • metabolized to inactive benzoylecgonine w/ half-life of 6 hrs (urine tests show positive up to a week after cocaine binge)

• w/ ethanol → active metabolite cocaethylene produced (half life = 3hrs)

  • is this why ~90% of cocaine users also drink alcohol, & may be alcohol dependent?

cocaine PharmD

• cocaine interferes w/presynaptic dopamine transporter (DAT) function

  • direct influence on mesolimbic “reward” pathway & basal ganglia (striatum) of the mesotriatal movement pathway

• cocaine = dopamine reuptake inhibitor

• VMAT = vesicular dopamine (monoamine) transporter 

heavy cocaine use: behavioral & brain abnormalities

• toxic paranoid psychosis: chronic cocaine use & amphetamine can cause symptoms resembling schizophrenia

  • paranoid delusion, auditory & visual hallucinations

  • hyperactivity, impulsiveness, aggression

  • formication: sensation of bugs crawling under skin (leads to scratching, sores, infections)

• reduced gray matter (aka → brain shrinkage) in numerous areas of cerebral cortex (e.g., OFC, anterior cingulate) 

cocaine addiction treatments: no good ones (yet!)

• dopamine agonists → can ease withdrawal symptoms, & reduce relapse;

  • e.g., buproprion (Wellbutrin) → antidepressant, reuptake inhibitor for DA

• glutamate/GABA regulation

  • ibogaine (Endabus): “dissociative” psychedelic acts as a Glu NMDA antagonist, many also affect 5-HT

  • topiramate (Topamax): an anticonvulsant GABA agonist, also prescribed for migraines 

amphetamines: discovery & history

• amphetamines synthesized from ephedra plant (→ opens lungs; sympathetic stimulator)

  • produce euphoria, wakefulness, increased concentration, reduced appetite

  • amphetamine molecule similar in shape to epinephrine

  • methamphetamines (methylated amphetamines) synthesized (1920)

• in 1930s → Benzedrine first marketed as inhaled antihistamine 

  • discovery of levo- & dexto- isomers

  •  Benzedrine was equal mix of l- & d- 

  • d- more potent, produced Dexedrine

• 1970s → abuse subsides => govt. pressure on drug companies to reduce production, “speed kills”, better depression treamtents cheaper c

amphetamines: PharmK

• administration → oral pill, nasal inhalation, smoking (e.g., methaphetamine “ice”), I.V.

• absorption → high lipid solubility. cross BBB very quickly

  • high concentrations enter the brain

  • esp. true of methamphetamine (stronger)

• distribution/metabolism → 12 hr half-life (compare to cocaine → ~45 mins)

• high probability of addiction compared to almost any other drug

  • tolerance develops quicly through all mechanisms

amphetamines: PharmD of DA & NE

• PNS → amphetamine is a powerful sympathomimetic

• CNS → either blocks dopamine transporters (DATs) or enters them to interfere with DA packaging (VMAT function)

• not shown here: similar effects (esp. @ high dose) at norepinephrine transporters (NETs) 

methamphetamine abuse: long-time use

• damage DA & 5-HT nerve terminals (including reduced DAT levels)

• some recovery of brain levels after abstinence of year or more → BUT there still may be behavioral details

  • slower motor function, Parkinson’s-like symptoms

  • memory deficits, depression, psychosis, paranoia

• Treatment? No successful pharmalogical approaches, most effective is behavioral, such as CBT & contingency management interventions (Motivational Incentives for Enhancing Drug Abuse Recovery (MIEDAR))

  • “token” system