Neuropharmacology & Behavior:

IntroductionBrian J. Piper, Ph.D.bpiper@willamette.edu

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Goals

• Course Overview

• Research resources

• Animal Research

• Pharmacokinetics

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

Writing your Research Paper

Essay Research Paper

Sources Tertiary Primary, some secondary

Tone Informal, personal opinion,

Uses “I”Formal

Quotes Yes Few (1-2/paper)

Abstract No Yes

End Bibliography References, APA format

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

Pubmed

• Developed by National Library of Medicine (NIH)

• http://www.ncbi.nlm.nih.gov/pubmed

Pubmed

Keywords are Important

Free is For Me!

Google Scholar

Specialized Databases

• Manage to bypass copyright law (how?)

• Example: Psychedelic Bibliography

• http://www.maps.org/sys/w3pb.pl?face=simple/

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

Ethics of Animal Use in Research and Teaching

Rules and Regulations

The primary responsibility when working with animals is to treat them humanely.

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?

Questionable Animal Research 2: Parabiosis

• Surgical means to create conjoined twins

• Used for behavioral endocrinology

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

1905-1981

1.5 min: http://www.youtube.com/watch?v=fg9QCeA4FJs

AWAAnimal 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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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

IACUCInstitutional 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

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.

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.

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.

Justification and Use of Animals

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.

Societal Decision (Pros)

Benefits to Humans• Vaccines• Antibiotics• Medical procedures• Space travel

• Benefits to Animals

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.

Societal Decision (Cons)

• Similarity to Humans – Chemistry– Anatomy– Pain?

• 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

Non-government Organizations• AALAS

– American Assoc. for Lab Animal Science

• AAALAC– Association for the Assessment and

Accreditation of Laboratory Animal Care

• ASLAP– American Society of Lab Animal

Practitioners• ACLAM

– American College of Lab Animal Medicine

• SCAW– Scientists Center for Animal Welfare

• PRIMR– Public Responsibility In Medicine and

Research

• NABR– National Assoc for Biomedical

Research• FBR

– Foundation for Biomedical Research

• ILAR– Institute of Lab Animal Resources

• AWIC– Animal Welfare Info Center

• ARENA– Applied Research Ethics National

Association• CAAT

– Center for Alternatives to Animal Testing

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

Interim Summary

• AWA (R-R-R)

4. Content!!

• Introduction

• Routes of drug administration

• Dose-Response Models

• Sensitization & Tolerance

• Drug Laws

How (many) drugs work: neurotransmission.

a.p. = action potential

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, Theobromine

Blocks adenosine

Entactogens MDMA, MDA Serotonin

Hullucinogens LSD, mushrooms Varied

Opiates Heroin, morphine, codeine, oxycodone

Endorphins

Stimulants Amphetamine,

cocaine

Dopamine

Group Examples Mechanism

Herbal Drugs Ginko, St. John’s wort

Varied

Sedatives Valium, GHB GABA

Steroids Testosterone,

androstenedione

Testosterone

Inhalants Gasoline, paints Varied

Nicotine Cigarettes, chewing tobacco

Acetylcholine

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

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)

3.1

ROA Example: Cocaine

Compare: time to reach maximum concentration (min)Vs.maximumconcentration(ng/ml)

Unit Label #

centi hundredth 10e-2

miili thousandth 10e-3

micro millionth 10e-6

nano billionth 10e-9

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.

Dose Response Models

• Threshold Model: This is the standard model in pharmacology. Increasing the dose beyond a certain point will produce a linear response.

• Caffeine example: Increasing the dose of caffeine will cause an increase response (e.g. heart rate).

Threshold Model

0

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a= NOEL

Hormesis Model

• Hormesis: the relationship between dose and response shows a non-linear or “J” shaped function, low doses produce the opposite effects of high doses.

• Alcohol Example: High doses of alcohol cause sedation and reduce motor activity. However, low doses increase activity.

Hormesis Model

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1 2 3 4 5 6

Dose

Resp

onse

Edward Calabrese

Tolerance/Sensitization

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

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.

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

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?

Schedule Medically

Approved Use

Abuse Potential Examples

I No High marijuana,

heroin, LSD

II Limited High cocaine, amphetamine

III Yes Moderate Steroids, Ketamine,

Marinol

IV Yes Moderate chance of physical dependence

Valium, Ambien

V Yes Low chance of physical dependence

Codeine

For more details, goto: http://en.wikipedia.org/wiki/DEA_Schedule_1

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

Summary

• Hormesis vs. Threshold

• Tolerance vs. Sensitization

• ROA on PK

• Schedules