Drugs & Behavior III: Amphetamines

Brian J. Piper, Ph.D.

Amphetamines

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Amphetamine Methamphetamine

Amphetamines

Amphetamine Methamphetamine

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3,4-methylenedioxymethamphetamine

Methyl: CH3; Methylene: CH2; Amine: organic compounds of Nitrogen,

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

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.montanameth.org/View_Ads/index.php

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

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

Other Faces of Methamphetamine

Robert Downey, Jr.Andre Agassi

Stacy Ann Ferguson “Fergie” Ted Arthur Haggard

Other Faces of Methamphetamine

http://www.erowid.org/chemicals/mdma/mdma.shtml

History of EcstasyEcstasy is 3,4-methylenedioxymethamphetamine (MDMA)

• 1912: Synthesized by German pharmaceutical company Merck by Anton Kollisch (1888-1916)

• 1950’s: U.S. Army conducted animals studies to determine the lethal dose.

• 1970’s: Mental health workers advocated using MDMA with psychotherapy. There are ongoing studies to use MDMA with talk therapy for anxiety related to post-traumatic stress disorder and among terminally ill cancer patients.

• 1985: Drug Enforcement Agency (DEA) classifies MDMA as Schedule I

• 1990’s- today: MDMA is popular recreational drug, especially among young-adults.

Short-term effects of Ecstasy

• Psychological– Empathy– Increased energy– Openness– Increased sensitivity to

sounds & touch

• Physiological– Increase in heart rate– Increase in blood pressure– Reduced appetite– Bruxism: grinding teeth– Trismus: jaw clenching

Example of tolerance• Rats received ecstasy

(MDMA) on 6 days. Arrows indicate times of administration.

• Panel A shows that MDMA altered 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.

Amphetamines

Amphetamine Methamphetamine

___

3,4-methylenedioxymethamphetamine

Methyl: CH3; Methylene: CH2; Amine: organic compounds of Nitrogen,

Chemistry

• Entactogen: touching within (Nichols)

Amphetamine

MDA (methylenedioxyamphetamine)

MDMA (methylenedioxymethamphetamine)

Ecstasy = MDMA?

Drug Levels in the Blood: Individual Differences Following Oral Administration of MDMA

Plasma MDMA for each marmoset thatreceived 1 mg/kg.

0 20 40 600

10

20

30

40

50

60

70

80

Eric

Autumn

Lexi

Zale

Time

MD

MA

(n

g/m

l)

Ng/ml

Age Influences How Your Body Responds to Drugs

MDMA -----> MDA

Meyer, Piper,& Vancolli (2010) Annals of the New York Academy of Sciences.

Brain Chemistry

• MDMA increases neurotransmitters (serotonin, norepinephrine, dopamine) & hormones (cortisol, prolactin)

Serotonin

• Serotonin is 5-hydroxytryptamine (5-HT)• The brain uses the amino acid tryptophan

(found in bananas, milk, yogurt) to make 5-HT.• 5-HT has been implicated in mood (anxiety,

depression & aggression), appetite, sexuality, and cognition.

See also: http://en.wikipedia.org/wiki/Serotonin

Raphe nuclei

• 5-HT cell bodies (somas) are found in the brainstem in the raphe nuclei.

• 5-HT axons descend into spinal cord and ascend to the hippocampus and cortex.

Serotonin Transporter (SERT)• SERT is a protein found at the synapse and

along the axon that removes 5-HT from the synaptic cleft.

• SERT (shown in pink) brings 5-HT from the synaptic cleft back into the axon.

• Serotonin reuptake inhibitors (e.g. Prozac or fluoxetine) prevent SERT from removing 5-HT.

• The density of SERT is used as a index of the number of 5-HT axons and is altered by MDMA.

Long-term effects of High Dose MDMA on 5-HT neurons (animal data)

• Weeks after MDMA treatment to animals, there is a reduction in 5-HT, 5-HT metabolites, and SERT which suggests a 5-HT axotomy (axons are cut).

• Months to years after MDMA in monkeys, some brain areas still show a reduction in SERT and 5-HT (hypoinnervation). However, other areas show an abnormal increase in SERT and 5-HT (hyperinnervation).

Serotonin fibers in the caudate nucleus of a control squirrel monkey (A), a monkey that received 5 mg/kg MDMA 2 weeks (B),

or 7 years (C) previously.

Hatzidimitriou, G. et al. J. Neurosci. 1999;19:5096-5107

What about brain function?

• Complex behaviors can be measured in non-human animals like:– Attention– Learning– Memory– “Emotion”

Object-Recognition Memory Task

Rats were exposed to two identicalobjects in a 3-min sample phase.

There was a retention delay (15 min),during which both objects were replaced:one replacement object was identical to theprevious two, while the other was a novelobject.

Memory of the familiar object isindicated by the animal spending moretime exploring the novel object during a3-min choice phase.

Figure from A. Ennaceur.

Adolescent MDMA decreases memory.

Saline MDMA

Sample (A) 25.6 (3.1) 23.5 (1.4)

Test (A) 11.8 (2.0) 14.9 (1.4)

Test (B) 24.7 (3.5) 20.0 (3.1)

B/(A+B) 0.68 (0.03) 0.56 (0.04)*

Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731

Adolescent MDMA reduces anxiety-like

behavior.

BEHAVIORSALINE-

TREATEDMDMA-

TREATEDP VALUE

Total arm entries 19.1 ± 3.0 27.4 ± 3.0 .074

Open-arm entries 3.1 ± 1.4 7.9 ± 1.8 .058

Open/Total (%) 12.8 ± 5.2 27.3 ± 5.3 .071

Open-arm duration (sec)

41.4 ± 18.7 108.9 ± 20.3 <.05

Closed-arm duration (sec)

507.4 ± 30.5 400.5 ± 30.3 <.05

Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731.

Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731.

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

MDMA Summary

• Short-Term Effects: – Empathy– hyperthermia, – ↑5-HT & Dopamine

• Long-Term Effects: ↓5-HT

Amphetamine Comparison

MDMA Methamphetamine

History One-century One-century

Acute Subjective Effects Empathy Euphoria

Neurotoxicity Serotonin Dopamine

Schedule I III

Addiction No Yes

Hallucinogens

Hallucinogens are psychedelic (mind-manifesting) drugs

that distort perceptions and evoke sensory images in the

absence of sensory input.

Ronald K

. Siegel

Hallucinogens

1. LSD: (lysergic acid diethylamide) powerful hallucinogenic drug that is also known as acid.

2. THC (delta-9-tetrahydrocannabinol): is the major active ingredient in marijuana (hemp plant) that triggers a variety of effects, including mild hallucinations.

http://static.how

stuffworks.com

Hemp Plant

DrugsSummary