neuropharmacology: stimulants

StimulantsBrian J. Piper, Ph.D.

Goals

• Examples– Methamphetamine– Cocaine– Khat

• Pharmacodynamics• Pharmacokinetics• Epidemiology• Overdose

Amphetamines

__

Amphetamine Methamphetamine

History of Amphetamine

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

She may be tired for either of two reasons:

*because she is physically overworked. If thisis 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 andemotional fatigue. For these patients, you mayFind “Dexedrine” an ideal prescription.

“Dexedrine” will give them a feeling of energyand well being, renewing their interest in lifeand living.

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

Pharmacodynamics

• Mechanisms– VMAT reversal– DAT reversal– DAT reuptake inhibition

Microdialysis for Dopamine (DA)

1.2

AMPH

1.0

0.8

0.6

0.4

0.2

080 160 240

Time (min)

700

600

500

400

300

200

100

0–40 0 40 80 120 160 200

0.75 mg/infusion0.50 mg/infusion0.25 mg/infusion0.00 mg/infusion

Time (min)

Increasein DA

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

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)

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.htmlhttp://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

Methamphetamine Epidemiology (MtF)

Past year use of crystal.

Year Year

% Reporting “fairly easy” or “very easy”to get.

Meth & Young-Adults

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

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

Flyers Posted at:* OHSU* Coffee shops, Book stores* Grocery stores* Drug Tx programs•Needle exchange programs•Crystal Meth Anonymous

Meth/Polysubstance Use

Unexposed (N=35) Exposed (N=31)

Trimesters of Methamphetamine 0 (0) 2.5 (0.3)***

Income while pregnant : <15,000Income currently : >35,000

17.1%51.4%

76.2*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 childrenIn home

2.7 (0.3) 1.3 (0.3)**

Piper et al. (2011) Pharm Biochem Behav

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

Memory IslandVisible (x 4)

Hidden (x 4)

Rizk-Jackson et al. (2006) Behav Brain Res 2006;173(2):181-90, Piper et al. Behav Brain Res.

Memory Island

Memory Island Performance is Reduced by Exposure

Increased Rates of ADHD

.

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.

*** p < .0005, ** p < .005, * p < .05 .

“Clinically Significant” Behavioral Problems in Exposed Children

Piper et al. (in review) Psychopharmacology.

Selectivity of Domains AlteredUnexposed 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

Blood levels of “Ice”

Blood level (ng/ml)

Hours

Spiders• Web building was

examined the day before and after stimulant administration.

Before After

Vehicle

0.04 uL/mgMethamphetamine

0.10 uL/mgCaffeine

Hesselberg & Vollrath (2004) Physiology & Behavior, 82, 519-529.

Araneus diadematus

History of Cocaine

• 1850s: Cocaine isolated from Erythroxylon coca• 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

1856-1939

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

Pharmacodynamics

• Reuptake inhibition of– DAT– NET– SERT

Short video of Cocaine and Neurotransmission: http://www.utexas.edu/research/asrec/cocaine.mov

Is cocaine addictive?• Cocaine withdrawal:

– does not produce physical symptoms

– does produce psychological symptoms:

• exhaustion• depressed mood• anhedonia• anxiety• craving

Other Neurotransmitters?

Immunostraining for DAT (A) or tyrsoineHydroxylase (B) in wild-type (+/+), hetero-Zygotous or DAT knock-out (-/-) mice.

Sora et al. (2001). PNAS, 95, 7699-7704.

Other Neurotransmitters?

Rocha et al. (1998) Nature Neuroscience, 1, 132-137.

Other Neurotransmitters (5-HT/NE)?

• Autoradiography using [123I]RTI55 & also with a SERT inhibitor (Alaproclate)

Rocha et al. (1998) Nature Neuroscience, 1, 132-137.

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.

DAWN ER Visits

Rank Me: Stimulants, MJ, Heroin, Cocaine

DAWN ER Visits

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.

Methylphenidate

• Treatment for ADD/ADHD• Blocks dopamine reuptake, increases norepinephrine• Pills crushed and snorted

Methylphenidate

C

O

OCH

N

CH3

MtF: “Amphetamines” =Adderall & Ritalin

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.

Cathinone

– active agent in Khat (or qat)– chewed– synthetic version (meth-

cathinone)

CH NH2C

CH3

O

Cathinone

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.

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

DA : dopamine, MAO: Monoamine oxidase

Methylphenidate = Ritalin

Top row: radioactive cocaine labelingBottom row: radioactive methylphenidate labeling

Basal Ganglia: brain area important for movement

Time course for cocaine (2, 4, 8, 10, 20, 30, & 40) orMethylphenidate (2, 4, 8, 10, 20, 30, 40, 60, 90) minutes

High is shown in green

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

Outliers: extreme scores statistically

Raclopride: drug that binds to D2 receptors

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

DA: dopamine receptor, autoreceptor: presynaptic

po: per os or by mouth (oral administration)

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

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

Effects of MP on Perception of the Task andCorrelations with MP-induced DA changes

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

Gr: tyros (cheese)amino acid

Treatment for

Parkinson’s

disease

Neurotransmitter important for movement, reinforcement

Neurotransmitter important for cognition

6.2