Lesson 18: Xanthine Stimulants

3 main methylxanthines

• caffeine

• theophylline → small amounts in nonherbal tea

• theobromine → found in chocolate

which type of coffee has the highest amount of caffeine

drip coffee

Neurophysiology - adenosine

• needed to make ATP for energy, and cAMP which is an important second messenger

• general used for neuroprotection (regulates nervous system) → most does not reach the synaptic cleft

• endogenous ligand mimicked by the methylxanthines

• methylxanthines are adenosine receoptor antagonists

Neurophysiology - adenosine receptors

• metabotropic

• 4 subtypes

  • 2 inhibitory

    • A1 → stimulates K+ efflux, inhibits cAMP production (Ca+ channels close)

    • A3 → inhibits cAMP production (Ca+ channels close)

  • 2 excitatory

    • A2A → stimulates cAMP production (Ca+ channels open)

    • A2B → stimulates cAMP production (Ca+ channels close)

Neurophysiology - adenosine receptor densities in the brain

• A1 found all over brain

  • major presence in HPX, cortex, and cerebellum

• A2A found mainly in striatum and olfactory bulb

• A2B and A3 not very common anywhere

Neurophysiology - adenosine receptor densities in the neuron

• postsynaptic

  • tends to inhibit action potential propagation due to the abundance of A1Rs

• presynaptic

  • tends to inhibits the release of other neurotransmitters including ACh, GLU, GABA, NE, 5-HT, DA

• may form a receptor mosaic → 2 different receptors attached to each other to influence each other; may change what the other does

Absorption + distribution

• primarily oral

• lipid soluble bases → rapid absorption from GI tract and no first pass metabolism

• easily crosses all barriers inside the body, and distributes equally

Elimination

• metabolized by the liver → less than 2% excreted unchanged

  • cytochrome P450 enzymes

• metabolic rate

  • slowed by alcohol, grapefruit juice, slower in nonsmokers, women taking oral contraceptives, and pregnant women

  • sped up by broccoli

  • newborns cant metabolize

Effects in the PNS

• vasodilation → blood vessels get larger

  • increased blood flow and heart rate

  • skeletal muscles strengthen

  • ANS controlled muscles relax

  • bronchial muscles dilate, increased rate and depth of breathing

Effects in the CNS

• vasoconstriction → blood vessels constrict in brain

  • relief of headaches in people with high blood pressure

  • relief of migrane symptoms by blocking adenosine

Other various effects

• feelings of well being, alertness, energy, motivation for repetitive work, self confidence

  • small doses

• anxiety, tremors, reduced sleepiness and fatigue

  • high doses

• reproduction → slower fetal development

• accelerates bone lass

• caffeinism → toxic reaction

  • can produce psychosis in healthy people

  • resolve with cessation

Effects on animal behavior

• increases spontaneous motor activity

• can act as a discriminative stimulus

• generality to other stimulants enables ‘turkey drugs’

  • drugs made of all legal ingredients, but intent to mimic effects of illicit drugs

• not a robust reinforcer → no self administer unless pretrained

  • different than humans

Tolerance

• develops quickly to most effects due to upregulation of adenosine receptors

• less effect on heavy coffee drinkers

• different effects show tolerance at different rates

• cross tolerance among methylxanthines

Withdrawal

• headache most common

• also possible → drowsiness, fatigue, low energy, impaired concentration, irritability, aches, muscle stiffness, decreased well being

• severity related to dose

• begins in 12-28 hrs, peaks at 21-51 hrs, lasts 2-9 days

Abuse liability

• very low

• DSM does not include caffeine use disorder

  • not clear if it is functionally impairing