# Presentation: 177780

## Monoamine Oxidase in Smoking:  Role in Addiction and Health

- Joanna S. Fowler
- Brookhaven National Laboratory

## Tobacco 

**Tobacco **

- Tobacco addiction is the largest cause of preventable mortality in the world
- Smoking leads to > 4 million smoking-related deaths annually (400,000 in US)
- 23% of US adults smoke
- There are nicotine and non-nicotine factors in cigarette addiction

**4000 chemical compounds in tobacco smoke**

## Addiction

- dopamine

- What we know...........

- All drugs abused by humans raise brain dopamine levels in the nucleus accumbens

- Dopamine is also elevated in feelings of well being and in anticipation of natural reinforcers like highly palatable food.

- From Nestler, Nature Neurosci, 2005

## Dopamine Neurotransmission

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**Time After Amphetamine**

**% of Basal Release**

**DA**

**Accumbens**

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**Time After Nicotine**

***Source: Di Chiara and Imperato***

**5 hr**

**hippocampus**

- Drugs elevate dopamine

- Natural reinforcers elevate dopamine

- DA cells

- Reward center

- judgement

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**Feeding**

***Di Chiara et al.***

- AMPHETAMNE

- NICOTINE

- FOOD

## The Brain Dopamine System

**anatomical slice**

**The Brain Dopamine System**

## Radiotracers for Brain Studies

**DA**

**signal**

**DA**

**DA**

**DA**

**DA **

**MAO A**

**Radiotracers for Brain Studies**

**MAO B**

- DA transporters

- DA receptors

- MAO B

- MAO A

- Nicotinic receptors

## Monoamine Oxidase

**RCH****2****NH****2** + O2 + H2O                RCHO + NH3 + **H****2****O****2**

- MAO

*MAO inhibitor drugs are used to treat depression and Parkinson's disease.*

- Two forms, MAO And B, break down **neurotransmitters** like dopamine, norepinephrine and serotonin (reward, mood, motivation)
- Produces **hydrogen peroxide** (a source of damaging free radicals)

## Smoking inhibits ~ 40% of MAO B in the human brain

## Brain MAO B and Smoking Status

- <date/time>

**    ****non-**
**smokers**

**smokers      former     L-deprenyl**
**                   ****smokers**

**MAO B (basal ganglia) **

**0**

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- MAO inhibition is caused by substances in tobacco.  Smokers also have low MAO A.

## Questions

- Do MAO levels recover after smokers abstain overnight?

## Tobacco Smoke Pharmacodynamics

**MAO B (********k****3****)**

**put     thl         fr         cb**

**single cigarette**

**non-smokers**

**baseline**

**cigarette**

## Does smoking also inhibit MAO in peripheral organs?

## MAO B in Peripheral Organs

- Smokers have 35-45% reduced MAO B in brain, heart, lungs, kidneys and spleen.

## Questions

- Does partial MAO inhibition in smokers contribute to the epidemiological features of smoking?
- What substance(s) in tobacco is inhibiting MAO? Nicotine does _not_ inhibit MAO!
- Would MAO inhibitors aid smoking cessation?
- (Berlin et al., 1996; George et al., 2003).
- Would MAO inhibition make nicotine and other drugs more reinforcing? (Stinus et al., 2005, 2006; Schiffer et al, 2003)

## Smoking Epidemiology

*Is tobacco smoke neuroprotective?*

## Isolation of MAO Inhibitors from Tobacco Leaves

**Farnesyl acetone**(Ki 0.8 μM (human liver, MAO B selective) (Khalil, Davies and Castagnoli, 2006)

**2,3,6-trimethyl-1,4-naphthoquinone**(Ki 3-6 μM (human liver, non-selective; protective against MPTP neurotoxicity in mice (Castagnoli et al., 2000, 2001))

## Who is at higher risk for smoking?

- Co-morbidity with Mental Illness

- 44% of all cigarettes consumed in the US are by individuals with a current psychiatric disorder
- 75% of patients in addiction and mental health treatment programs smoke cigarettes

## Smoking Epidemiology

- Normal healthypopulation:				23% (US)
- 					67(4) (China)
- 					64(44) (Turkey)
- alcoholism:				90%+
- other addictions:			90%+
- schizophrenia:			85%
- depression:			80%

*Are smokers self-medicating?*

## X

- RCH2NH2 + O2 + H2O                RCHO + NH3 + H2O2

- MAO

- protects neurotransmitters
- lowers hydrogen peroxide

## MAO B Inhibition to Treat Smoking Addiction

- George et al., Biological Psychiatry 53: 136-143, 2003

- Could MAO B inhibition account for some of the psychoactive properties of tobacco?
- Can MAO B inhibition help the smoker who wants to quit?

- MAO B inhibition is effective in smoking cessation

## Would MAO inhibitors make nicotine and other drugs more reinforcing?

**DA**

**DA**

**DA**

**DA**

**DA**** **

**DA**** **

**DA**

**signal**

**MAO B**

**MAO A**

- smoker

- non-smoker

## Chronic MAO B inhibition by L-deprenyl enhances the response to cocaine

- Cocaine Challenge on MAO B-Inhibited Rats
*in vivo* Microdialysis (Schiffer et al., 2003)

## Summary

- Imaging studies have shown that smokers have reduced MAO in brain and peripheral organs
- Low brain MAO may account for some of the behavioral and epidemiological features of smoking
- Non-nicotine factors in cigarette addiction merit more investigation to understand why people smoke and to use this knowledge for smoking prevention and cessation

## Addiction and Public Health

- cancer

- accidents

- obesity

## Brookhaven Center for Translational Neuroimaging  

- Brookhaven Center for Translational Neuroimaging

- Funded by DOE-OBER, NIH, GCRC and ONDCP

**David Alexoff, Karen Apelskog, Helene Benveniste,Anat Biegon, Elisabeth Caparelli, Pauline Carter, Stephen Dewey, Congwu Du, Richard Ferrieri, Joanna Fowler, John Gatley, Andrew Gifford, Rita Goldstein, Bud Jayne, Kun-eek Kil, Sunny Kim, Payton King, Nelly Klein, Aarti Kriplani, Jean Logan, Jeming Ma, Martine Mirrione, Lisa Muench, Colleen Shea, Wynne Schiffer, David Schlyer, Mike Schueller, Dardo Tomasi, Frank Telang, Paul Vaska, Nora Volkow, Gene-Jack Wang, Donald Warner, Chris Wong, Youwen Xu, Wei Zhu **http://www.bnl.gov/CTN/

**(funded by DOE-OBER, NIH and ONDCP)**