Lecture 1 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Covers writing a research paper, routes of administration, writing a research paper, animal research ethics, neurochemistry.

1. Neuropharmacology
& Behavior:
Introduction
Brian J. Piper, Ph.D.
bpiper@willamette.edu
Hit F5 to view show (for PCs).

2. Goals
• Course Overview
• Research resources
• Animal Research
• Pharmacokinetics

3. 1. Course Objectives
• Drugs: legal and illicit, recreational and “everyday”
• Psychobiology: Brain + Behavior relationships can be studied using
drugs as tools
• Homework: NPR
• Written communication
– Primary sources: Studies
– Secondary sources: Reviews
– Tertiary sources:
• Newsweek
• Online organizations where author’s name is NOT known (e.g. NIDA, Erowid)
• Newspaper
• Wikipedia

4. Writing your Research Paper
Essay Research Paper
Sources Tertiary Primary, some secondary
Informal, personal opinion,
Tone Formal
Uses “I”
Few (1-2/paper)
Quotes Yes
Abstract No Yes
Bibliography References, APA format
End

5. 2. Literature Search
• Wikipedia (preliminary only, variable quality)
• Google (heavy on $)
• Pubmed (Backward Search)
• Psych Info (Backward Search)
• Specialized databases (Backward Search)
• Google Scholar (Forward Search)
• Also: Direct contact

6. Pubmed
• Developed by National Library of Medicine
(NIH)
• http://www.ncbi.nlm.nih.gov/pubmed

7. Pubmed

9. Keywords are Important

10. Free is For Me!

11. Google Scholar

12. Specialized Databases
• Manage to bypass copyright law (how?)
• Example: Psychedelic Bibliography
• http://www.maps.org/sys/w3pb.pl?face=simple/

13. All Journals Aren’t Created
Equal
Great! Not Great!
Science (30.1) Psychological Reports (0.3)
Nature (29.8) Neuroreport (1.9)
New England J Medicine (53.5) J of Psychoactive Drugs (1.3)
Am J Public Health (4.2) Life Science (2.5)
J Amer Med Association (30.0)
Proceed Nat Acad Science (4.8)
Psychopharmacology (3.8)
Neuropharmacology (3.9)
Neuropsychopharmacology (6.7 ) International J of …. , SW Missouri
Newsletter
Impact Factor: # citations per manuscript per year

14. Ethics of Animal Use in
Research and Teaching

15. Rules and Regulations
The primary
responsibility when
working with
animals is to treat
them humanely.

16. Questionable Animal Research
1: Foot shock induced
aggression
• Mild footshock to paired rats results in
fighting
• Used to study effects of hormones,
temperature, drugs
• Justified?

17. Questionable Animal Research
2: Parabiosis
• Surgical means to create conjoined
twins
• Used for behavioral endocrinology

18. Questionable Animal Research
3: Harry Harlow & monkey love
• Tested food versus contact comfort
• Important for adopted children
• Animal rights movement is a reaction to
his research
1.5 min: http://www.youtube.com/watch?v=fg9QCeA4FJs
1905-1981

19. AWA
Animal Welfare Act
• 1966, amended in most recently in 2007
• Regulates use of dogs, cats, hamsters, guinea pigs,
rabbits, farm animals, marine mammals, and non-
human primates in research and teaching (rats, mice,
and birds are currently not regulated, but probably will
be in the near future).
• The regulations cover the procurement, handling,
treatment, and transportation of these animals.

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22. AWA enforcement
• Enforced by the Animal and Plant Health
Inspection Service of the United States
Department of Agriculture (USDA)
– Unannounced annual on-site inspections
– Inspects all facilities, relevant records, and
documentation
– Progressive series of disciplinary actions for
non-compliance, including citations, warning,
fines, court orders, loss of registration

23. IACUC
Institutional Animal Care and Use Committee
• Reviews animal use
proposals
• Conducts semi-annual
inspections of animal
facilities
• Investigates concerns
about animal care and
use
• Can suspend research
or teaching activities
when a major violation
has occurred

24. IACUC membership
• A veterinarian who is certified in
laboratory animal medicine.
• At least one practicing scientist who is
experienced with research and training
involving animals.
• A least one member of the public to
represent general community interests
in the proper care and use of animals.

25. Role of IACUC
• To protect animal welfare.
• To protect the University.
• To assist in maintenance of a productive
research environment.
• To utilize peer review in evaluation of
protocols and inspection of animal
facilities.

26. Animal Care and Use
Protocols
• Rationale and purpose of the
proposed use of animals.
• Justification of the need to use
animals, the species of animal chosen
and the number of animals requested.
• Adequacy of training and experience
of personnel.
• Housing and care of animals.
• Pain and distress
• Method of disposition of the animals
at the end of the study.

27. Justification and Use of
Animals

28. The Three R’s
• Legislated by the AWA
• Replacement
– Substitution of other models for animals (or
substitution of a less sentient species for a more
sentient one)
• Can the hypothesis be tested or the training be done with
cell cultures, computer simulations, or other non-animal
system?
• Reduction
– What is the minimum number of animals that can
still yield statistically valid outcomes?
• Can you work with a statistician to determine this?
• Refinement
– What efforts are being made to eliminate or
minimize animal pain and distress?
• Anesthesia, analgesia and alternate experimental design must be considered.

29. Societal Decision (Pros)
Benefits to Humans
• Vaccines
• Antibiotics
• Medical procedures
• Space travel
• Benefits to Animals

30. Hair Analysis
• Some rhesus monkeys exhibit self-abusive behavior
(SIB)
• Cortisol, a stress hormone, levels were examined in
monkeys
Davenport et al. (2008). Biological Psychiatry, 63, 990-996.

31. Societal Decision (Cons)
• Similarity to Humans
– Chemistry
– Anatomy
– Pain?

32. • Association for the Assessment and
Accreditation of Laboratory Animal Care
– This is a volunteer organization that works with research
organizations to ensure the highest standards of animal care
and use.
– They emphasize appropriate veterinary care, in-depth oversight
by IACUC, protection of the health of animals.
– Full accreditation by AAALAC considered one of the best
professional achievements in the field of lab animal care

33. Non-government
• AALAS Organizations
• NABR
– American Assoc. for Lab – National Assoc for
Animal Science Biomedical Research
• AAALAC • FBR
– Association for the – Foundation for Biomedical
Assessment and Research
Accreditation of Laboratory • ILAR
Animal Care – Institute of Lab Animal
• ASLAP Resources
– American Society of Lab • AWIC
Animal Practitioners – Animal Welfare Info Center
• ACLAM • ARENA
– American College of Lab – Applied Research Ethics
Animal Medicine National Association
• SCAW • CAAT
– Scientists Center for Animal – Center for Alternatives to
Welfare Animal Testing
• PRIMR
– Public Responsibility In
Medicine and Research

34. The Guide for the Care and
Use of Laboratory Animals
• Describes institutional
responsibilities for
animal care and use
• Provides guidelines for
designing and operating
an animal care program

35. Interim Summary
• AWA (R-R-R)

36. 4. Content!!
• Introduction
• Routes of drug administration
• Dose-Response Models
• Sensitization & Tolerance
• Drug Laws

37. How (many) drugs work:
neurotransmission.
a.p. = action potential

38. Types of Different Drugs
• Drug = any chemical put into the body that changes mental state or
bodily function (Kuhn, 2003)
Group Example Mechanism
Xanthines Caffeine, theophylline, Blocks adenosine
Theobromine
Entactogens MDMA, MDA ⇑ Serotonin
Hullucinogens LSD, mushrooms Varied
Opiates Heroin, morphine, Endorphins
codeine, oxycodone
Stimulants Amphetamine, ⇑ Dopamine
cocaine

39. Group Examples Mechanism
Herbal Drugs Ginko, St. John’s Varied
wort
Sedatives Valium, GHB GABA
Steroids Testosterone, Testosterone
androstenedione
Inhalants Gasoline, paints Varied
Nicotine Cigarettes, Acetylcholine
chewing tobacco

40. Routes of administration (ROA)
• Oral (p.o.): caffeine, alcohol
• Inhaled: THC
• Injected (hypodermic syringe: Alexander Wood-1853)
– Intravenously (i.v.): heroin
– Subcutaneous (s.c.): occasionally heroin
– Intramuscularly (i.m.): steroids
• Topical: nicotine patch
• Sublingual: LSD
• Other: intrathecal, rectal, vaginal, eye

41. 3.1
ROA Determines Blood Levels
• Different routes of
administration produce
different levels of drug in the
blood
• In general:
– Injection: quick, drug levels
peak soon and come down
rapidly (green)
– Inhalation: also very quick
(red)
– Oral: absorbed and
eliminated more slowly (blue)

42. ROA Example: Cocaine
Unit Label #
centi hundredth 10e-2
miili thousandth 10e-3
micro millionth 10e-6
nano billionth 10e-9
Compare:
time to reach
maximum
concentration
(min)
Vs.
maximum
concentration
(ng/ml)

43. Half-Life
• Half-life: the amount of time that 50% of drug is
eliminated
• Example: Caffeine has a half-life of 3 hours
– In 3 hours, 50% of caffeine is removed
– In 6 hours, 75% is removed (half of remaining 50%)
– In 9 hours, 87.5% is removed
– In 12 hours, 93.75% is removed, and so on
• Drug elimination depends on the biological matrix
– Drugs are eliminated most quickly from the blood but may be
detected at longer intervals in urine, feces, sweat, saliva, or hair.

44. 2.5
Dose Response Models
• Threshold Model: This is the Threshold Model
standard model in 8
pharmacology. Increasing the 7
6
dose beyond a certain point 5
Response
will produce a linear response. 4
3
• Caffeine example: Increasing 2
the dose of caffeine will cause 1 a
0
an increase response (e.g. 1 2 3 4 5 6
heart rate). Dose
a= NOEL

45. Hormesis Model
• Hormesis: the Edward Calabrese
relationship between
dose and response
shows a non-linear or “J” Hormesis Model
shaped function, low
14
doses produce the 12
opposite effects of high 10
doses. 8
Response
• Alcohol Example: High 6
4
doses of alcohol cause 2
sedation and reduce 0
motor activity. However, 1 2 3 4 5 6
low doses increase Dose
activity.

46. Tolerance/Sensitization
• The response to a drug can change with
repeated administration.
– Sensitization: a heightened response
– Tolerance: a reduced response

47. Example of tolerance
• Rats received ecstasy
(MDMA) on 6 days.
Arrows indicate times of
administration.
• Panel A shows that
MDMA effected core
temperature on the 1st
day.
• Panel B shows that the
same dose had less
effects on the 3th day.
• Panel C shows almost no
effects by the 6th day.
Piper et al. (2005) Developmental Psychobiology, 47, 145-157.

48. Mechanisms of Tolerance
• Tolerance can result from one of more factors
– Pharmacokinetic Tolerance: pharmacokinetics is the
study of drug metabolism, tolerance could be caused
by the drug being eliminated from the blood more
quickly
– Pharmacodynamic Tolerance: pharmacodynamics is
the study of how drugs act a cellular level, there could
be a reduced response by neurons
– Psychological Tolerance: classical conditioning
processes

49. Schedule of Drugs
• U.S. federal government developed a system to classify drugs,
Comprehensive Drug Abuse Prevention and Control Act of 1970
describes different schedules (I to V)
• Scheduling is based on:
– Medically approved use: Is there a disease that the drug is effective in
treating?
– Abuse Potential: What is the likelihood that the drug will be abused?

50. Schedule Medically Abuse Potential Examples
Approved Use
I No High marijuana,
heroin, LSD
II Limited High cocaine,
amphetamine
Steroids, Ketamine,
III Yes Moderate Marinol
Moderate chance Valium, Ambien
IV Yes of physical
dependence
Low chance of Codeine
V Yes physical
dependence
For more details, goto: http://en.wikipedia.org/wiki/DEA_Schedule_1

51. What’s in a name?
Chemical Brand Street
Fluoxetine hydrochoride Prozac happy pills
Methylphenidate Ritalin Vitamin R
Oxycodone Oxycontin Oxy, Hillbilly Heroin
Clonazepam Klonopin K-pin

52. Summary
• Hormesis vs. Threshold
• Tolerance vs. Sensitization
• ROA on PK
• Schedules