# Presentation: 537666

## Smoking:Neurochemical Systems Beyond Dopamine

- Julie K. Staley, Ph.D.
- Division of Brain Imaging
- Department of Psychiatry

## Smoking & Serotonin

- High rate of history of depression [Glassman et al., 1990; 1993] & negative affect [Pomerleau & Pomerleau, 1984; Hughes, 1988;Carmody et al., 1989]
- Genetic link between anxiety, depression and nicotine dependence [Kendler et al., 1993;Lerman et al. 1996]
- Well established role for serotonin in anxiety, mood, and appetite
***Hypothesis: Serotonergic systems plays a pathological role in smoking behavior***

## Tobacco Smoke & Serotonin

_**_________________________________________**_
***Via its actions on the cholinergic nicotinic receptor, nicotine indirectly***** **
- 			**5-HT**** ****reuptake **(platelet#***;**brain@)
- 			**5-HT release **(platelet*;brain^)
*An unknown component of tobacco smoke*
- 			**MAO-A activity****&**
**NET EFFECT**   **5-HT neurotransmission**
_**_________________________________________**_
- #Schievelbein et al., 1967; *Rausch et al., 1989; @King et al., 1991; ^Ribeiro et al., 1993;&Essman, 1977;Yu and Boulton, 1987

## Status of 5-HT Synapse in Smokers

_**________________________________________________**_
**MAO-A****!**
**5-HT** (Platelet*Urine#)
**5-HIAA** (Urine)#
**5-HT****1A**** Receptor **(Brain^)
**5-HT****2A**** Receptor** (Platelet@; Brain^)   **/(-)**
**5-HT Transporter****	****	****                  ?**
_**________________________________________________**_
**!**Fowler et al., 1996;*Marasini et al., 1986;Racke et al., 1992; #Sparrow et al., 1992; ^Benwell et al., 1990;@Markowitz et al., 1999

## 5-HT Transporter

**Located on 5-HT cell bodies in the raphe nuclei, and on 5-HT terminal projections throughout the basal ganglia, diencephalon and cerebral cortex.**
**Functions to regulate 5-HT signaling by modulating 5-HT levels in the synapse.**
**Principal target of many antidepressants ****(Montgomery et al., 1995)**
**Some evidence for increased frequency of the short variant of the 5-HT transporter gene in mood disorders ****(Collier et al., 1996, Ogilvie et al. ,1996)**

**5-HTT**

**5-HT****2A/C**

**5-HT****1A**

**5-HT****1A**

-  Tryptophan
- 5-OH-tryptamine
- Serotonin

**5-HT****1A**

**5-HT****2A/C**

**PCPA**

## 5-HTTLPR Genotype & Smoking

**Association between smoking and 5-HTTLPR (l/s or l/l) in Japanese** [Ishikawa et al., 1999]
**Interaction between (s/s or s/l) 5-HTT gene, & high neuroticism score **[Hu et al., 2000; Lerman et al., 2000]
**an average chance of initiating smoking**
**higher risk of becoming addicted upon smoking**
**more difficult to quit smoking**
**Personality scores and 5-HTTLPR genotype may predict the clinical efficacy of certain smoking cessation drugs e.g. SSRIs.**

## SSRIs for Smoking Cessation

**Fluoxetine**
**ameliorates depressive symptoms in smokers**** **[Dalack et al., 1995]
**prevents increased food intake & weight gain**** **[Hitsman et al., 1999]
**increased abstinence rates in smokers with elevated BDI scores**, **but not those with lower BDI scores when used as an adjunct to NRT** [Blondal et al., 1999]
**Paroxetine**
**Reduced craving  and depressive symptoms with more pronounced effects in smokers with a history of MDD when given in combination with NRT** [Killen et al., 2000]

## Demographics							

**	****	****	****	****Age****	**** ****	****BMI****	****	****SES**
_**	**__**	**__**	**__**	**__**(y)**__**	**__**	**__**(kg/m**__**2**__**)_______**__**	**_
***Total  (n = 21/group)***
**Nonsmokers****	****	****40.0 **_**+**_** 11.0****	****27.4 **_**+**_** 5.5****	****2.6 **_**+**_** 1.0**
**Smokers****	****	****	****40.4 **_**+**_** 10.7****	****26.7 **_**+**_** 6.2****	****3.4 **_**+**_** 0.7**
***Female (n =12/group)***
**Nonsmokers****	****	****40.7 **_**+**_** 11.5****	****26.5 **_**+**_** 4.5****	****2.8 **_**+**_** 0.9**
**Smokers****	****	****	****40.5 **_**+**_** 11.4****	****27.1 **_**+**_** 7.9****	****3.3 **_**+**_** 0.6**
***Male (n = 9/group)***
**Nonsmokers****	****	****39.2 **_**+**_** 10.9****	****28.7 **_**+**_** 6.6****	****2.3 **_**+**_** 1.0**
**Smokers****	****	****	****40.2 **_**+**_** 10.2****	****26.1 **_**+**_** 3.5****	****3.6 **_**+**_** 0.9**
**________________________________________________________________________________________________________________________________________________________________________**
**The mean **_**+ **_**S.D. is shown. BMI-Body Mass Index; SES-Socioeconomic Class.**

## Characteristics of Smokers (1)

**	****	****	****   ****Total  ****	****	****Female ****	****Male**
**	****	****	**** ****(n = 21)****	****	****(n=12) ****	**** (n=9)**
_**________________________________**__**	**__**	**__**	**_
**Age Began **
**Smoking (yrs)       16.3 **_**+**_** 3.1****	****15.3 **_**+**_** 3.1****	****16.8 **_**+**_** 3.1**
**# Yrs Smoked       24.5 **_**+**_** 10.0****	****25.3 **_**+**_** 11.0****	****23.6 **_**+**_** 9.1**
**# Cigarettes/day   23.6 **_**+**_** 4.3****	****23.9 **_**+**_** 4.2****	****23.1 **_**+**_** 14.6****	**
**# Pack-years****	****28.9 **_**+**_** 13.0****	****30.4 **_**+**_** 14.8****	****26.9 **_**+**_** 10.6**
**________________________________________________________________________________**
**The mean **_**+**_** SD is shown.**

**Characteristics of Smokers (1)**

## Characteristics of Smokers (2)

_**________________________________________________**_
**	****	****  ****	**** ****Total  ****	****	****Female ****	****	****Male ****	**
**	****	****	**** ****(n = 21)****	**** ****	****(n=12)****	****	****(n=9)**
_**_________________________________________________**_
**FTND****	****     5.1 **_**+**_** 1.7****	****	****5.1 **_**+**_** 1.6****	****	****5.2 **_**+**_** 2.0**
**Cotinine ****	****     293 **_**+**_** 104****	****270 **_**+**_** 86****	****	****323 **_**+**_** 123**
**QSU****	****	****    32.8 **_**+**_** 13.7****	****35.9 **_**+**_** 14.9****	****	****28.6 **_**+**_** 11.3**
**NWS****	****      ****	****    11.1 **_**+**_** 12.5****	****9.6 **_**+**_** 12.2****	****	****13.2 **_**+**_** 13.4**
**_________________________________________________ **
**The mean **_**+**_** SD is shown.**

**Characteristics of Smokers (2)**

## Mood Scores

**	****	****Total****	****	****Nonsmokers****	****Smokers**
**______________________________________________________**
**Negative Mood**
**Total****	****	****	****	****1.2 **_**+**_** 9.1 (14)****	****         4.2 **_**+**_** 8.1 (17)***
**Male ****	****        4.2 **_**+**_** 10.4 (13) ****	****4.0 **_**+**_** 12.0 (7)****	****         4.5 **_**+**_** 9.3 (6)**
**Female        1.8 **_**+**_** 7.1 (18)****	****-1.6 **_**+**_** 4.5 (7)            4.0 **_**+**_** 7.8 (11)**
**BDI**
**Total****	****	****	****	****    0 (14)                   4.0 **_**+**_** 4.5 (17)****
**Male ****	****	****2.5 **_**+**_** 4.8 (13)****	****     0 (7)****	****        5.5 **_**+**_** 5.9 (6)**
**Female****	****1.9 **_**+**_** 3.2 (18)       0 (7)****	****        3.2 **_**+**_**3.6 (11)**
**______________________________________________________**
**(*Mann Whitney p < 0.05;**Mann Whitney p  < 0.001).**

**Mood Scores**

## MRI & SPECT

**MRI & SPECT**

## Higher Diencephalon [123I]-CIT Uptake in Females vs Males (p = 0.008).No Change in Smokers vs Nonsmokers

***Total***

***Females***

***Males***

## Higher Brainstem [123I]-CIT Uptake in Females vs Males (p = 0.013) &Male Smokers vs Male Nonsmokers (p = 0.046)

***Total***

***Males ***
**** p < 0.05***

***Females***

## SERT Levels by Sex in Nonsmokers and Smokers

**Group****	****	****Total ****	****	****Nonsmokers****	****	****Smokers**
_***________________________________________________________***_
** ****Diencephalon V****3****”**
**Total  ****	****	****	****	****2.03 **_**+**_** 0.36 (21)****	****2.07 **_**+**_** 0.33 (21)**
**Female   2.17 **_**+**_** 0.31 (24)****	****2.18 **_**+**_** 0.30 (12)****	****2.16 **_**+**_** 0.34 (12)**
**Male ****	****    1.89 **_**+**_** 0.33 (18)****	****1.82 **_**+**_** 0.36 (9) ****	****1.96 **_**+**_** 0.29 (9)****	**** **
**Brainstem V****3****”****	**
**Total  ****	****	****	****	**** 0.99 **_**+**_** 0.20 (21)****	****1.09 **_**+**_** 0.18 (21) **
**Female  1.10 **_**+**_** 0.17 (24)****	****1.08 **_**+**_** 0.14 (12)****	****1.13 **_**+**_** 0.20 (12)**
**Male ****	****  0.87 **_**+**_** 0.22 (18)         0.87 **_**+**_** 0.22 (9)****	****1.04 **_**+**_** 0.14 (9)**
_**__________________________________________________________**__**	**__**	**_
**The mean **_**+ **_**S.D. is shown for [****123****I]********-CIT uptake in brainstem expressed as V****3****”**** = [(VOI) –cerebellum)/ cerebellum]. The number (n) of subjects in each group is shown in parentheses**

**SERT Levels by Sex in Nonsmokers and Smokers**

## Summary: SERT in Smokers

**No effect of smoking on diencephalic SERT**
**Modest increase (10%) brainstem SERT in smokers versus nonsmokers. **
**No significant sex* smoking status in diencephalon however **
-  20% higher SERT in male smokers vs nonsmokers
-  < 5% difference between female smokers & nonsmokers**  **

## Summary: Serotonin & Smoking

**Tryptophan hydroxylase gene link to initiation of smoking behavior**** **[Lerman et al., 2001; Sullivan et al., 2001]
**5-HTLLPR-s association with neuroticism and smoking **[Lerman et al., 2000; Hu et al., 2000]
**motivation to reduce negative mood**
**smoking for stimulation**
**Preliminary finding of sex-specific decrease in SERT availability in male smokers- **
**Improvements in mood from SSRI treatment in smokers with depressive symptoms **

## Summary: Serotonin & Smoking

**Further studies that include **
**genetics**
**neuroimaging of SERT using a more selective radiotracer**
**treatment with SSRIs **
**   ****studied in concert including an assessment of sex differences are needed to understand the role of the SERT in the pathophysiology of tobacco smoking.**

## Acknowledgments

_**Patient Recruitment**_**	****	****	**_**Chemists**_
**Stephanie O’Malley, PhD****	****	****Ronald Baldwin, PhD**
**Suchitra Krishnan-Sarin,PhD****	****	****Gilles Tamagnan, PhD ****	**
**Suzanne Giddings ****	****	****	****Sami Zogbhi, PhD**
**Michele Frascatore****	****	****	****Louis Amici**
**Eva Mathews****	****	****	****	****Nina Sheung**
**Nadique Morrison****	****	****	****	**
**Angelo Termine ****	****	****	****	**** **_**NeuroSPECT/IND**_
**Rachel Torello ****	****	****	****	**** John Seibyl, MD**
**	****	****	****	****	**** ****Michele Early**
**	****	****	****	****	**** ****Andrea Perez****	****	**
_**Computer Assistance**_**	****	****	**** John Macmullen**
**Quinn Ramsby****	****	****	****                Eileen Smith**
**Mohammed Al Tikriti****	****	****               Gary Wisenski**
** **
_**Statistics:**_
**Paul K. Maciejewski, Ph.D. ****	****        ****Robert B. Innis, MD, PhD**
***Supported by MRSDA K01 AA00288, the Transdisciplinary Tobacco Research Center P50 DA 84733; the Donaghue Women's Health Investigator Program at Yale, and the VA Mental Illness Research, Education, and Clinical Center*****.**

## DAT Levels by Sex in Nonsmokers & Smokers

**Group****	****Total ****	****	****Nonsmokers****	****	****Smokers**
_**______________________________________**__**	**__**_________ **_
**V****3****”**
**Total ** 			    6.78 _+_ 1.09 (21)   6.75 _+_ 0.82 (21)
**Female    **7.05 _+_ 0.97 (24)   7.09 _+_ 1.12 (12)  7.01 _+_ 0.83 (12)
**Male**	      6.38 _+_ 0.80 (18)    6.36 _+_ 0.94 (9)	  6.40 _+_ 0.7 (9)
_**__________________________________________________**_
- The mean _+_ S.D. is shown. The number (n) of subjects in each group is shown in parentheses.***Male vs female  p = 0.025.**

**DAT Levels by Sex in Nonsmokers & Smokers**

## Higher Striatal [123I]-CIT Uptake in Females vs Males (p = 0.025)No Change in Smokers vs Nonsmokers

***Total***

***Females***

***Males***