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Smoking:Neurochemical Systems Beyond Dopamine

Smoking:Neurochemical Systems Beyond Dopamine. Julie K. Staley, Ph.D. Division of Brain Imaging Department of Psychiatry. Smoking & Serotonin.

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Smoking:Neurochemical Systems Beyond Dopamine

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  1. Smoking:Neurochemical 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, 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

  3. Tobacco Smoke & Serotonin _________________________________________ Via its actions on the cholinergic nicotinic receptor, nicotine indirectly 5-HTreuptake (platelet#*;brain@) 5-HT release (platelet*;brain^) An unknown component of tobacco smoke MAO-A activity& NET EFFECT5-HT neurotransmission _________________________________________ #Schievelbein et al., 1967; *Rausch et al., 1989; @King et al., 1991; ^Ribeiro et al., 1993;&Essman, 1977;Yu and Boulton, 1987

  4. Status of 5-HT Synapse in Smokers ________________________________________________ MAO-A! 5-HT (Platelet*Urine#) 5-HIAA (Urine)# 5-HT1A Receptor (Brain^) 5-HT2A 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. 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

  6. 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.

  7. 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]

  8. Demographics Age BMI SES (y) (kg/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.

  9. 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.

  10. 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.

  11. 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).

  12. 1. Radiotracer Synthesis 2. Radiotracer Injection 3. Plasma Parent & Metabolites 4. SPECT & STEP Scan MRI SPECT MRI & SPECT

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

  14. Higher Brainstem [123I]b-CIT Uptake in Females vs Males (p = 0.013) &Male Smokers vs Male Nonsmokers (p = 0.046) Females Males * p < 0.05 Total

  15. 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 [123I]b-CIT uptake in brainstem expressed as V3” = [(VOI) –cerebellum)/ cerebellum]. The number (n) of subjects in each group is shown in parentheses

  16. 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

  17. 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

  18. 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.

  19. Acknowledgments Patient RecruitmentChemists 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.

  20. 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 [123I]b-CIT Uptake in Females vs Males (p = 0.025)No Change in Smokers vs Nonsmokers Total Females Males

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