Methylxanthines and Nootropics

Question 1

Caffeine

Answer 1

• methylxanthine
• most consumed behaviourally active substance
• similar but milder effects as classic psychostimulants (motor activation, arousal, concentration, wakefulness)
• seems to potentiate dopamine system

Question 2

Guaranine or Metaeine

Answer 2

• “organic alternative to caffeine”

- chemically identical to caffeine but comes from different sources (yerba mate and guarana plants)

Question 3

General Physiological Effects

Answer 3

• increase release of NTs 9including adrenaline)
• activation of cortex
• dilation of blood vessels in periphery but constriction of cranial vessels (has complicated bp effect, forces oppose each other)
• relaxation of smooth muscle, stimulation of skeletal muscle
• diuretic (300+ mg), increase blood flow to kidneys, weakens bladder, inhibits resorption of water and sodium

Question 4

Is it a cognitive enhancer?

Answer 4

• depends on test whether inhibits or enhances learning and memory
• increases if tired or bored (help stay awake and concentrate) but doesn’t improve beyond level of rested brain doing not bring task

Question 5

What is adenosine? What effect does caffeine have to adenosines effects?

Answer 5

• neuromodulator
• decreases release of NTs (calming effect)
• presynaptically prevents NTs release and postsynaptically depressant effects
• caffeine prevents all of these effects by binding to receptor (blocks calming effect leads to stimulant effect)

Question 6

What does caffeine do?

Answer 6

• antagonist at adenosine receptors
• A1 and A2A seem to be most important for caffeine effects (most effects due to A1 likely, A2A involved in process of keeping you awake)

Question 7

A1 vs A2A receptors

Answer 7

A1: presynaptic, inhibits cAMP, inhibits NT release, distributed thoughout brain
A2A: both pre and post synaptic, stimulates cAMP productions, promotes NT release (GABA), mostly in NAcs

Question 8

Effects on sleep

Answer 8

• if drink caffeine at night pushes back sleep wake cycle 45 minutes
• adenosine levels climb during waking until point this is reached that triggers sleep
• adenosine binding to A2A receptors in the hypothalamus trigger GABA release (inhibits arousal system)
• caffeine prevents adenosine from binding to A2A receptors, prevents GABA release, inhibit sleep

Question 9

At higher doses what else does caffeine target?

Answer 9

• inhibits phosphodiesterase (PDE) enzymes which metabolize cAMP (get increased cAMP)
• > results in relaxation of smooth muscle (vasodilation) and increase contraction of heart muscles
• inhibits GABA-A receptors (seizures)
• increases calcium channel function (more Ca2+ in cell so more likelihood of NT release)
• > increase work capacity of muscle

Question 10

Which is the most important target?

Answer 10

(dose and effect graph in notes)

• A1 and A2A primary target (at normal levels of caffeine probably only these)
• some suggest PDE as well
• other effects like (PDE, Ca2+, and GABA-A) only at toxic dose generally (unlikely to take this much

Question 11

Metabolism of Caffeine

Answer 11

• liver
• 3 primary metabolic products:
  1) paraxanthine (increases lipolysis, leads to elevated glycerol and free fatty acids in blood plasma)
  2) theobromine (dilates blood vessels and increases urine volume)
  3) theophylline (relaxes airway smooth muscle)

Question 12

Is it a drug of abuse?

Answer 12

• robust dopamine increase in the nucleus accumbens
• seems due to block of A1 receptors that normally inhibit dopamine and glutamate release (so get increase DA and Glu (which further increases DA levels))

Question 13

Caffeinism

Answer 13

• preoccupation with and overuse
• agitation, anxiety, muscle twith, heart palpitations, increased temperature
• abrupt termination leads to symptoms

Question 14

How much caffeine is lethal?

Answer 14

10 g (100 cups of coffee)
-death from convulsion, respiratory arrest

Question 15

Health risks

Answer 15

• seizures in young people
• osteoporosis (neg effects on bone density)
• > increases urinary excretion of calcium and inhibits absorption from diet
• increased risk of panick attacks (mostly in those with specific mutation in A2A receptor)

Question 16

Health benefits

Answer 16

• chances of getting Parkinson’s lower in people that drink caffeine
• effects dose related (cuts risk almost 5 fold)

Question 17

Nootropics

Answer 17

• thought to be cognitive enhancers
• normally used as therapy of cognitive deficit diseases (eg Alzheimer’s, stroke)
• Many types, work via variety of NT systems
• students using to study concentrate
• > don’t know if actually work (depend on what is measured)
• in cog disorder long term effects are replacement of NTs/neurons, unknown what long term effects are in healthy

Question 18

Memantine

Answer 18

• low affinity reversible NMDA receptor antagonist
• in pts with neurodegeneration: stop excess activation of NMDA receptors which kill neurons (paradox b/c memory depends on activation of receptors)
• in healthy: decrease background glutamate “noise” while still allowing for receptors to be activated when glutamate is released from nerve endings
• side effects: confusion, dizziness, headache, constipation, body aches

Question 19

Rivastigmine

Answer 19

• acetylcholinesterase inhibitor
• inhibits enzyme break down of acetylcholine
• used clinically as cog enhancer for neurodegenerative diseases (where there is a loss of ach releasing neurons)
• side effects: diarrhea, confusion, dizziness, hallucinations, seizures, irregular heart beat, severe nausea
• evidence in healthy humans mixed