Neuropharmacology: Caffeine

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Lecture 13 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Includes pharmacokinetics and pharmacodynamics.

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Neuropharmacology: Caffeine

  1. 1. CaffeineBrian J. Piper, Ph.D.
  2. 2. Goals • Structure of different xanthines • Pharmacokinetics • Psychological and Physiological Effects • Pharmacodynamicshttp://en.wikipedia.org/wiki/Caffeine
  3. 3. Coffea aribica Coffea robusta Botany • Coffea aribica: grown in Brazil, 10 m tall, 7 years to mature • Coffea robusta (Coffea canephora): grown in Vietnam, < 1 year to mature, 2 x caffeine ● Camellia sinensis: grown in China, 2 m tall, leaves = 4% caffeine ● Theobroma cacoa: grown in Mexico, 6 m tall, contains theobromine, dogs Theobroma cacao Camellia sinensis http://en.wikipedia.org/wiki/Camellia_sinensis http://www.ico.org/botanical.asp
  4. 4. Structure• Xanthine: group of mild stimulants, Xanthine forms backbone• Methly Group: a Carbon & 3 Hydrogens (CH3)• Theobromine: Xanthine + two methyl groups (3,7)• Theophylline: Xanthine + two methyl groups (1,3)• Caffeine: Xanthine + three methyl groups (1,3,7)
  5. 5. Structure• Caffeine: Xanthine + three methyl groups (1,3,7)• CYP1A2: removes methyl groups
  6. 6. Energy Drinks Serving Size Caffeine (mg) (oz.)Spike Shooter 8.4 300Cocaine 8.4 280Monster Energy 16 160Full Throttle 16 144Rip It, all varieties 8 100Enviga 12 100Tab Energy 10.5 95SoBe 8 83Red Bull Sugarfree 8.3 80Rockstar Energy Drink 8 80SoBe Adrenaline Rush 8.3 79Amp 8.4 74Glaceau Vitamin Water Energy Citrus 20 50SoBe Essential Energy, Berry or Orange 8 48 http://www.cspinet.org/new/cafchart.htm Accessed 3/15/08
  7. 7. http://anrcatalog.ucdavis.edu/pdf/8265.pdf
  8. 8. Seizures?• Rats that were genetically prone to convulsions received different doses (umol/kg) of methylxanthines.• Behavior was rated for 6 hours: – 0 = no response – 2 = tremor – 4 = forelimb clonus – 6 = falling down – 8 = tonic-clonic seizures/death *Clonus (Gr: violent, confused motion), large involontary movementsDe Sarro et al. (1997) Naunyn-Schmiedeberg’s Arch Pharmacol, 356, 48-55.
  9. 9. Seizures?• Rats that were genetically prone to convulsions received different doses (umol/kg) of methylxanthines. *Clonus (Gr: violent, confused motion), large involontary movementsDe Sarro et al. (1997) Naunyn-Schmiedeberg’s Arch Pharmacol, 356, 48-55.
  10. 10. Sex Differences in Caffeine PK <-women, non-smoking • Women and men received 100 mg caffeine capsules. • Women (open circles) had men, smoking -> <-men, non-smoking higher caffeine levels than men (open-squares). • Sex differences were apparent in both plasma and saliva. • Smoking: increases CYP1A2 • Oral Contraceptives: inhibit CYP1A2Carrillo et al. (2000).Ther Drug Monitor, 22, 409-417.
  11. 11. Smoking Difference in Caffeine PK <-women, non-smoking • Smoking: increases CYP1A2 • Oral Contraceptives: inhibit CYP1A2 men, smoking -> <-men, non-smokingCarrillo et al. (2000).Ther Drug Monitor, 22, 409-417.
  12. 12. Caffeine-Melatonin CYP1A2 InteractionCaffeine increased:Cmax 2.4AUC 2.2 Plasma melatonin levels in humans after melatonin administer either alone (circles) or preceeded by 3 x 200 mg or caffeine (squares). Hartter (2003). Brit J Clin Pharmacology, 56, 679-682.
  13. 13. Effects• Psychological • Physiological – Increased alertness – Constricts blood – Improved attention vessels in brain and – Euphoria (slight) eyes. – Nervousness (High – Increases heart rate Doses) – Elevates urine production – Increases breathing rate
  14. 14. Cognitive Benefits • Medical students (N=18) completed tests of vigilance or sleepiness at baseline, after placebo,150 mg caffeine, or caffeine + 2 g taurine. • Both caffeine & caffeine + taurine improved performanceAggarwal et al. (2011). Brit J Surgery, 98, 1666-1672.
  15. 15. Caffeine & Reinforcement Preference ---------------------------------- AversionPatkina & Zvartau Eur J Neuropsychopharm, 8, 287-291.
  16. 16. Pharmacodynamics • Adenosine antagonist • Increases dopamine & glutamate • Elevates adrenaline (epinephrine) • Blocks antidiuretic hormoneFor more details about neurobiological effects of caffeine, goto:http://images.google.com/imgres?imgurl=http://www.benbest.com/health/A_Recept.gif&imgrefurl=http://www.benbest.com/health/caffeine.html&h=288&w=429&sz=29&tbnid=yC5aX2S9XqKrbM:&tbnh=82&tbnw=123&hl=en&start=12&prev=/images%3Fq%3Dadenosine%26svnum%3D10%26hl%3Den%26lr%3D%26rls%3DCNDB,CNDB:2004-15,CNDB:en%26sa%3DN
  17. 17. Adenosine• has 24 hour rhythm
  18. 18. Neurochemistry• Caffeine causes biphasic effects on nucleus accumbens neurotransmitters and behavior. Solinas, M. (2002). et al. J. Neurosci 22, 6321-6324
  19. 19. Caffeine Tolerance• Caffeine abstaining humans (N=18) lived in a lab for two-weeks – Day 1-3: all placebo – Day 4-10: 250 mg caffeine or placebo – Day 11-14: placebo Robertson et al. (1981) J Clin Invest , 67, 1111-1117.
  20. 20. Tolerance to otherPhysiological Effects <- Day 1 <- Day 7Robertson et al. (1981) J Clin Invest , 67, 1111-1117.
  21. 21. Caffeine Tolerance • Rats received caffeine (1.0, Dose 0.25, or 0 mg/ml drinking water) for two-weeks. • They were then dosed with caffeine, adenosine antagonists (CPT or MSX) or amphetamine. • Motor activity was recorded. • How do you interpret this data? Caffeine in Water for 2 weeksKarcz-Kubicha et al (2003) Neuropsychopharmacology, 28, 1281-1291.
  22. 22. Interpretation• What information is provided by: – A versus B – B versus C – D versus E versus F – G versus H B D E G F C H A
  23. 23. Interpretation• In rats that were caffeine naïve, caffeine caused hyperactivity (A vs. B).• Rats that regularly consumed caffeine were insensitive/tolerant to caffeine (B vs. C).● There was no cross- tolerance to the B hyperactivity caused by amphetamine(D vs. E vs. F). D E● Adenosine is important G F for caffeine tolerance. Caffeine pre- exposed rats also showed a blunted hyperactivity to the C H A1 and A2A antagonists (G vs H). A
  24. 24. Caffeine & Parkinson’s Disease (PD)? • Dietary habits were obtained from middle aged men (N=8,000) in 1965. • Subjects were monitored for 30 years for incidence of PD. • Mechanisms – Antioxidant – 3rd variableParkinson’s Symptoms (2 min):http://www.youtube.com/watch?v=_L_WF6gv5BIRoss, G. W. et al. (2000). JAMA, 283, 2674-2679.
  25. 25. Tri-methyl-xanthine Summary• Pharmacokinetics (CYP1A2)• Pharmacodynamics – Adenosine antagonist• Risks (seizures?)• Benefits (Parkinson’s Disease?)
  26. 26. Self-test• Jane drinks two large (12 oz) cups of instant coffee with breakfast, a Starbucks cafe latte in the afternoon, a Coke (12 oz) with dinner, and a decaf coffee (8 oz) while studying before bed.• What was her total (mg) of caffeine consumption for the day? Please show how you reached this total using the chapter in Buzzed.

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