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Prevalence of Smoking in Psychiatric Disorders (PD) and Substance Abuse Disorders (SUD)

Prevalence of Smoking in Psychiatric Disorders (PD) and Substance Abuse Disorders (SUD). Kalman D, Morrisette SB, and George, TP Am J Addiction, 106-123, 2005. Nicotinic Acetylcholine Receptors (nAChR). Ligand gated ion channel Pentamer α and β subunits

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Prevalence of Smoking in Psychiatric Disorders (PD) and Substance Abuse Disorders (SUD)

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  1. Prevalence of Smoking in Psychiatric Disorders (PD) and Substance Abuse Disorders (SUD) Kalman D, Morrisette SB, and George, TP Am J Addiction, 106-123, 2005

  2. Nicotinic Acetylcholine Receptors (nAChR) • Ligand gated ion channel • Pentamer • α and β subunits • Twelve known subunits α 2-10 and β2-4 • Two main types present in brain • α7 nAChR subtype • High affinity for α- bungarotoxin • α4β2 nAChR subtype • High affinity for nicotine • Believed to upregulate in response to nicotine

  3. 2*-nAChRs in the Reward Pathway Dopamine Nicotine b2-nAChR Ventral Tegmental Area Ventral Striatum

  4. [123I]5-IA-85380 [5-iodo-3-(2(S)-azetidinylmethoxy)pyridine] • High affinity for neuronal nAChRs • High selectivity for nAChR with the β2 subunit • Low nonspecific binding • Dissociates slowly from the receptor • Readily crosses the blood brain barrier • Low toxicity Musachio 1998, 1999; Fujita 2000; Horti 1999; Mukhin 2000

  5. Subtype Selectivity of nAChR Ligands Mukhin,… London et al. Mol. Pharmacol. 2000

  6. [123I]5-IA SPECT measurement of 2*-nAChR in brain (Staley et al., J Nuc Med, 2005)

  7. Evidence nAChRs upregulate • Nicotine, the primary addictive chemical in tobacco smoke, upregulates the nicotinic acetylcholine receptor (nAChR). • This has been shown postmortem in human tobacco smokers (Breese et al., 1997; Court et al., 1998). • Confirmed in animal studies after chronic nicotine exposure(Kassiou et al., 2001, Marks et al., 1992). • Due to changes in receptor density, Bmax, as opposed to changes in receptor affinity, KD (Peng et al., 1994; Marks et al., 1983). • The changes in receptor density may underlie tobacco smoking tolerance and dependence.

  8. Nicotine blocks [123I]5-IA binding in nonhuman primates Urine cotinine levels (ng/mL) were measured withNicoMeter™ test strips (Staley et al., J Neuroscience 2006)

  9. Higher cortical 2*-nAChR in abstinent smokers vs. never smokers 60 60 - - 50 50 - - 40 40 - - Never Smoker (Female, 31 yo) 30 30 - - 20 20 - - 10 10 - - Smoker (Female, 32 yo ), Abstinent 7 days (Staley et al., J Neuroscience 2006)

  10. Evidence nAChRs normalize over time Preclinical: nicotine binding returns to control levels between 7 days and 3 weeks abstinence depending on the route of administration and dosing regimen (Marks et al., 1985; Pietila et al., 1998; Ksir et al., 1985). Postmortem: smokers who quit at least 2 months prior to death had nicotine binding levels similar to controls (Breese et al., 1997). In vivo: the upregulation was shown to be temporary, decreasing by 21 days of abstinence(Mamede et al., 2007).

  11. The purpose was to examine 2*-nAChR availability in tobacco smokers over the course of abstinence. STUDY 1 • Smokers were scanned up to 4 times….. 1 week, 4 weeks, 6-12 weeks 1 day, 1 week, 2 weeks, 4 weeks Cosgrove…..Staley, Arch Gen Psych, 2009

  12. Abstinence from smoking Smokers were helped to remain abstinent with contingency management techniques. Abstinence was confirmed twice daily for the first 8 days with carbon monoxide and urine cotinine measurements. Urine Cotinine levels (ng/mL) Carbon monoxide levels (ppm) Measured with NicAlert™

  13. 1. Radiotracer Synthesis MRI & SPECT 2. Radiotracer Injection 3. Metabolism & protein binding 4. SPECT & STEP Scan MRI SPECT

  14. [123I]5-IA SPECT regions of interest AC Anterior Cingulate Medial FC FC Frontal Cortex Cd Caudate Temporal Cortex CB TIC Pt Putamen FC AC FC AC Th Thalamus PC Parietal Cortex Cerebellum OC Occipital Cortex

  15. Outcome Measure VT/fp = radioactivity in brain /blood Receptor “availability” • Receptors that are free or available to be bound by the radiotracer. • It is not a measure of all receptors, because some could be occupied by acetylcholine or nicotine.

  16. Subject Characteristics

  17. 2*-nAChR availability in smokers normalizes over the course of prolonged abstinence Cosgrove…..Staley, Arch Gen Psych, 2009

  18. 2*-nAChR availability in brain during acute abstinence

  19. 2*-nAChR availability in brain during prolonged abstinence 20% decrease from 1-12 wk

  20. 2*-nAChR availability in brain over time in abstinent smokers

  21. 160- 125- Smokers 1 Day Smokers 1 Week Smokers 2 Weeks Smokers 4 Weeks Smokers 6-12 Weeks Nonsmokers 90- 55- 20- It takes up to 6-12 weeks for receptors to “normalize”

  22. Negative correlation between 2*-nAChR availability and craving Relief of Negative Affect or Withdrawal/Urge to smoke 1 wk Staley et al., 2006 4 wks Cerebellum Cosgrove et al., 2009

  23. Summary Study 1 Normalization of the nAChR…….. • is prolonged in humans • varies between individuals • may be genetically-mediated

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