Lecture 18 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Focus is on the pharmacokinetics, pharmadynamics, and epidemiology.

1. Stimulants
Brian J. Piper, Ph.D.

2. Goals
• Examples
– Methamphetamine
– Cocaine
– Khat
• Pharmacodynamics
• Pharmacokinetics
• Epidemiology
• Overdose

3. Amphetamines
_
_
Amphetamine Methamphetamine

4. History of Amphetamine
• 1887: first synthesized by L. Edeleano
• 1932: SKF introduces Benzedrine
• 1970s: peak use in the U.S.

5. She may be tired for either of two reasons:
*because she is physically overworked. If this
is the case, you prescribe rest because rest is
the only cure for this kind of physical tiredness
*because she is mentally “done in”. Many of
your patients---particularly housewives---are
crushed under a load of dull, routine duties
that leave them in a state of mental and
emotional fatigue. For these patients, you may
Find “Dexedrine” an ideal prescription.
“Dexedrine” will give them a feeling of energy
and well being, renewing their interest in life
and living.

6. Amphetamine Sensitization
• Rats given 2.0 mg/kg of
d-amphetamine once
per day for 10 days
• Measure amount of
drug-induced rotational
behavior each day

7. Pharmacodynamics
• Mechanisms
– VMAT reversal
– DAT reversal
– DAT reuptake inhibition

8. Microdialysis for Dopamine (DA)
1.
2 0.75 mg/infusion
700 0.50 mg/infusion
1. 0.25 mg/infusion
0 600 0.00 mg/infusion
0.
8
500
Increase 0.
400
6
in DA 300
0.
4
200
AMPH
0.
2 100
0
0
80 160 240 –40 0 40 80 120 160 200
Time (min)
Time (min)

9. History of Methamphetamine
• 1893: Synthesized by Nagai Nagayoshi in Japan
• 1940s- : Popular with military
• 1960s- : used for short-term treatment of obesity, narcolepsy,
and, later, ADHD
• 1983- : federal and states laws attempt to reduce use by
decreasing availability of ephedrine and pseudoephedrine
• 2000s- : several aggressive advertising campaigns are aimed
at reducing demand

10. History of Methamphetamine
• 1893: Synthesized by Nagai Nagayoshi in Japan
• 1940s- : Popular with military
• 1960s- : used for short-term treatment of obesity, narcolepsy,
and, later, ADHD
• 1983- : federal and states laws attempt to reduce use by
decreasing availability of ephedrine and pseudoephedrine
• 2000s- : several aggressive advertising campaigns are aimed
at reducing demand (Faces of Methamphetamine)

13. Montana Meth Project
• Businessman Thomas
Siebel supported
graphic advertising in
2005
• Goal was to reach each
teenager 3+
times/week (TV, radio,
print).
To View Ads:
http://www.methproject.org/ads/tv/tracy.html
http://www.montanameth.org/View_Ads/index.php

14. True of False: “the MMP results in Montana
have been more significant than any other drug
prevention program in history”?
Youth Risk Behavior Survey
• High School students were
asked about lifetime
methamphetamine use
before and after the
Montana
Methamphetamine Project.
Anderson (2010) J Health Econ

15. True or False:
“the MMP results in Montana have
been more significant than any other drug
prevention program in history”?
Youth Risk Behavior Survey
• High School students were
asked about lifetime
methamphetamine use
before and after the
Montana
Methamphetamine Project.
Anderson (2010) J Health Econ

16. Other Faces of
Methamphetamine

17. Other Faces of Methamphetamine
Andre Agassi
Robert Downey, Jr.
Ted Arthur Haggard
Stacy Ann Ferguson “Fergie”

18. Methamphetamine Epidemiology (MtF)
% Reporting “fairly easy” or “very easy”
to get.
Past year use of crystal.
Year Year

19. Meth & Young-Adults

20. Meth & Spatial Memory In Rodents
• Rodent research has found that early developmental
Methamphetamine treatments cause persistent impairments in
spatial memory.
Acevedo SF, de Esch IJ, Raber J (2007) Neuropsychopharmacology 32:665-672

21. Flyers Posted at:
* OHSU
* Coffee shops, Book stor
* Grocery stores
* Drug Tx programs
•Needle exchange program
•Crystal Meth Anonymous
Exclusion Criteria:
* born before 35 weeks
gestational age
* epilepsy
* Tourette’s syndrome
* cerebral palsy
* congenital abnormalities
* severe brain trauma
* Fetal Alcohol Syndrome
* uncorrected visual impairments

22. Meth/Polysubstance Use
Unexposed (N=35) Exposed (N=31)
Trimesters of Methamphetamine 0 (0) 2.5 (0.3)***
Income while pregnant : <15,000 17.1% 76.2*
Income currently : >35,000 51.4% 60.0%
Maternal Age at Birth (years) 26.9 (1.1) 29.8 (1.5)
Nicotine 17.1% 76.2***
Alcohol 11.4% 71.4%***
Marijuana 11.4% 58.8%*
Biological father involved 85.7% 44.8%***
Number of other children 2.7 (0.3) 1.3 (0.3)**
In home
Piper et al. (2011) Pharm Biochem Behav

23. Reduced Academic Performance in
Exposed Children
Unexposed (N=35) Exposed (N=31)
Birth Weight (g) 3,279 (114) 3,367 (194)
Females 42.9% 53.3%
Ethnicity (% non-Caucasian) 25.7% 20.0%
Age at testing (7-9) 8.4 (0.2) 8.1 (0.2)
Below Grade Level (%) 3.0% 25.9%*
Below Reading Level (%) 20.6% 38.5%
Piper et al. (2011) Pharm Biochem Behav .

24. Memory Island
Visible (x Hidden (x 4)
4)
Rizk-Jackson et al. (2006) Behav Brain Res 2006;173(2):181-90, Piper et al. Behav Brain Res.

25. Memory Island

26. Memory Island Performance
is Reduced by Exposure

27. Increased Rates of ADHD
.

28. Behavioral Rating Inventory of Executive
Function (BRIEF)
• Please rate whether the following behaviors are
never, sometimes, or often a problem (1-3 points):
– Emotional Control (EC) : overreacts to small problems
– Inhibit (INH): interrupts others
– Shift (SHI): becomes upset with new situations
– Working Memory (WM): when given three things to do, remembers only the first or last
– Initiate (INI): has trouble coming up with ideas for what to do in play time
– Plan/Organize (PO): gets caught up in details and misses the big picture
– Organization of Materials (OM): cannot find things in room
– Monitor (MON): does not check work for mistakes
– Behavioral Regulation Index + Metacognition Index =
Global Executive Composite (Mean= 50.0, SD = 10)
Gioia GA, Isquith PK, Guy SC, et al. (2000). Behavioral Rating Inventory of Executive Function: Professional Manual. Psychological Assessment Resources: Lutz.

29. “Clinically Significant” Behavioral Problems in Exposed Children
*** p < .0005, ** p < .005, * p
< .05 Piper et. al. (in review) Psychopharmacology .

30. Selectivity of Domains Altered
Unexposed Exposed
IQ (WASI) 104.5 (3.7) 95.1 (3.5)#
Vocabulary 51.0 (2.2) 46.3 (1.7) #
Matrix Reasoning 53.8 (1.9) 48.4 (2.2) #
Block Design 52.7 (2.2) 50.0 (1.8)
Spatial Span (Forward) 5.7 (0.3) 5.3 (0.3)
Spatial Span (Backward) 4.9 (0.4) 4.5 (0.4)
Family Pictures (Immediate) 57.0 (5.3) 46.5 (5.1)
Family Pictures (Delayed) 52.6 (5.7) 43.4 (5.1)
#
p < .10
Piper et al. (2011) Pharm Biochem Behav

31. Blood levels of “Ice”
Blood level
(ng/ml)
Hours

32. Spiders
• Web building was Before After
examined the day
before and after
Vehicle
stimulant
administration.
Araneus diadematus
0.04 uL/mg
Methamphetamine
0.10 uL/mg
Caffeine
Hesselberg & Vollrath (2004) Physiology & Behavior, 82, 519-529.

33. History of Cocaine
• 1850s: Cocaine isolated from Erythroxylon coca
1856-1939
• 1880s: Sigmund Freud evolves from strong cocaine proponent
(therapy for heroin addiction, antidepressant) to become more
cautious & stops using (migraines) in 1896
• 1904: Cocaine is removed as an ingredient from Coca Cola

34. History of Cocaine
• 1984: Crack emerges in LA, NY, & Miami
• 1985: Sentencing laws, 500 g cocaine or 5 g crack = 5 years, 100:1!
• 2010: Fair Sentencing Act (Kucinich & Paul): 18:1
Keith Haring, 1958-1990
http://www.youtube.com/watch?v=ytJpZguSy2U

35. Pharmacodynamics
• Reuptake inhibition of
– DAT
– NET
– SERT
Short video of Cocaine and Neurotransmission:
http://www.utexas.edu/research/asrec/cocaine.mov

36. Is cocaine addictive?
• Cocaine withdrawal:
– does not produce
physical symptoms
– does produce
psychological
symptoms:
• exhaustion
• depressed mood
• anhedonia
• anxiety
• craving

37. Other Neurotransmitters?
Immunostraining for DAT (A) or tyrsoine
Hydroxylase (B) in wild-type (+/+), hetero-
Zygotous or DAT knock-out (-/-) mice.
Sora et al. (2001). PNAS, 95, 7699-7704.

38. Other Neurotransmitters?
Rocha et al. (1998) Nature Neuroscience, 1, 132-137.

39. Other
Neurotransmitters
(5-HT/NE)?
• Autoradiography using
[123I]RTI55 & also with a SERT
inhibitor (Alaproclate)
Rocha et al. (1998) Nature Neuroscience, 1, 132-137.

40. Conditioned Place Preference
• CPP to cocaine is present in
DAT or SERT knock-outs
• Double knock-outs do not
show CPP
Sora et al. (2001). PNAS, 98, 5300-5305.

41. DAWN ER Visits
Rank Me: Stimulants, MJ, Heroin, Cocaine

42. DAWN ER Visits

43. Comparison
Cocaine Methamphetamine
Schedule II (surgery) II (ADHD)
Base form “crack” “crystal”
Half-life (hours) 1 11
Metabolite Benzoylecgonine (BE) amphetamine
Mechanism(s) DA, NE, 5-HT uptake inhibition DA, NE, 5-HT uptake
inhibition + release
Julien (2009) Primer of drug action.

44. Methylphenidate
• Treatment for ADD/ADHD
• Blocks dopamine reuptake, increases norepinephrine
• Pills crushed and snorted
O
CH C O CH 3
N
Methylphenidate

45. MtF: “Amphetamines” =
Adderall & Ritalin

46. Juvenile Methylphenidate alters CPP to cocaine
Rats received methylphenidate (2 mg/kg) or saline as juveniles (PD 20-35) followed by
cocaine in adulthood (PD 60). Juvenile methylphenidate altered the conditioned place
preference (A) and locomotor (B) responses to cocaine.
Anderson et al. (2001) Nature Neuroscience, 5,13-14.

47. Cathinone
– active agent in Khat (or qat)
– chewed
– synthetic version (meth-
cathinone)
O
C CH NH 2
CH 3
Cathinone

48. PET images from control subjects, Parkinson’s patients,
and abstinent methamphetamine and methcathinone users
(average period of abstinence, 3 years). WIN-35,429
binding to the dopamine transporter.
Neurotoxicity?
McCann et al. (1998). J Neurosci 18, 8417-8422.

49. Sympathomimetic Summary
• Pharmacokinetics
• Pharmacodynamics: DA, NE, 5-HT
• Epidemiology
Nora Volkow “Mechanisms Underlying Use and Abuse of Stimulant Drugs”
http://videocast.nih.gov/summary.asp?Live=1997

50. DA : dopamine, MAO: Monoamine oxidase

51. Methylphenidate = Ritalin

52. Top row: radioactive cocaine labeling
Bottom row: radioactive methylphenidate labeling
Basal Ganglia: brain area important for movement

53. Time course for cocaine (2, 4, 8, 10, 20, 30, & 40) or
Methylphenidate (2, 4, 8, 10, 20, 30, 40, 60, 90) minutes

54. High is shown in green

55. DA: dopamine; MAO A: monoamine oxidase, type A

57. Outliers: extreme scores statistically

60. Raclopride: drug that binds to D2 receptors

63. Top: DAT Occupancy by dose (mg/kg)
Bottom: self-rated high by dose (mg/kg)

65. DA: dopamine receptor, autoreceptor: presynaptic

67. po: per os or by mouth (oral administration)

70. DA: dopamine, DAT: dopamine transporter, MP: methylphenidate

71. Microdialysis for DA (dopamine) following stress, methylphenidate,
or stress + methylphenidate

73. Effects of MP on Perception of the Task and
Correlations with MP-induced DA changes

74. Effects of Methylphenidate (MP) when given with a Mathematical or a Neutral Task on
[11C]raclopride binding, coditions: Placebo + Neutral task; MP + neutral task, Placebo +
Mathematical Task, Methylphenidate + Mathematical task

75. Gr: tyros
6.2 (cheese)
amino acid
Treatment for
Parkinson’s
disease
Neurotransmitter important for
movement, reinforcement
Neurotransmitter important for
cognition