Smoking:Neurochemical Systems Beyond Dopamine

1
SmokingNeurochemical Systems Beyond Dopamine

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

2
Smoking Serotonin

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

3
Tobacco Smoke Serotonin

• _________________________________________
• Via its actions on the cholinergic nicotinic
  receptor, nicotine indirectly
• 5-HT reuptake (plateletbrain_at_)
• 5-HT release (plateletbrain)
• An unknown component of tobacco smoke
• MAO-A activity
• NET EFFECT 5-HT neurotransmission
• _________________________________________
• Schievelbein et al., 1967 Rausch et al., 1989
  _at_King et al., 1991 Ribeiro et al.,
  1993Essman, 1977Yu and Boulton, 1987

4
Status of 5-HT Synapse in Smokers

• ________________________________________________
• MAO-A!
• 5-HT (PlateletUrine)
• 5-HIAA (Urine)
• 5-HT1A Receptor (Brain)
• 5-HT2A Receptor (Platelet_at_ Brain) /(-)
• 5-HT Transporter ?
• ________________________________________________
• !Fowler et al., 1996Marasini et al., 1986Racke
  et al., 1992 Sparrow et al., 1992 Benwell et
  al., 1990_at_Markowitz et al., 1999

5
5-HT Transporter
Tryptophan 5-OH-tryptamine Serotonin
PCPA

• 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-HT1A
5-HT1A
5-HT2A/C
5-HT1A
5-HT2A/C
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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.

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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

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Demographics Age BMI SES (y) (k
g/m2)_______ 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.
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Characteristics of Smokers (1)
________________________________ Total
Female Male (n 21) (n12)
(n9) ________________________________ 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.
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Characteristics of Smokers (2)
________________________________________________
Total Female Male (n 21)
(n12) (n9) ___________________________________
______________ 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.
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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 lt 0.05Mann Whitney p lt 0.001).
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MRI SPECT
13
Higher Diencephalon 123Ib-CIT Uptake in Females
vs Males (p 0.008).No Change in Smokers vs
Nonsmokers
Females
Total
Males
14
Higher Brainstem 123Ib-CIT Uptake in Females
vs Males (p 0.013) Male Smokers vs Male
Nonsmokers (p 0.046)
Males p lt 0.05
Females
Total
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SERT Levels by Sex in Nonsmokers and Smokers
__________________________________________________
______ Group Total Nonsmokers Smokers ________
________________________________________________
Diencephalon V3 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
V3 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
123Ib-CIT uptake in brainstem expressed as V3
(VOI) cerebellum)/ cerebellum. The number
(n) of subjects in each group is shown in
parentheses
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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
• lt 5 difference between female smokers
  nonsmokers

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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

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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.

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Acknowledgments
Patient Recruitment Chemists Stephanie
OMalley, 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.
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DAT Levels by Sex in Nonsmokers Smokers
__________________________________________________
Group Total Nonsmokers Smokers _______________
_______________________ _________ V3 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.
21
Higher Striatal 123Ib-CIT Uptake in Females vs
Males (p 0.025)No Change in Smokers vs
Nonsmokers
Total
Females
Males