1. Emerging Neuronal Nicotinic Receptor Targets Marina Picciotto Department of Psychiatry Yale University School of Medicine

2. What does nicotine bind to in the brain?

3.      muscle type nicotinic receptor  x  x  y  y  y neuronal type nicotinic receptors  z  z  z  z  z Structure of nicotinic ACh receptors

4. Lenovere and Changeux, 1995 Nicotinic acetylcholine receptor subunits

5. Where in the brain are nicotinic receptors found?

6. Nicotinic subunit in situ - cortex/thalamus

7. Nicotinic subunit in situ - VTA

8. GLU DA Ventral tegmental area Nucleus accumbens  7 subunit containing nAChR  2 subunit containing nAChR  nicotine  dopamine Nicotine regulation of the DA system GABA

9. Nicotine effects on DA neurons

12. What does smoking do to nicotinic receptors?

13. + nicotine - nicotine 3 H-nicotine 3 H- cytisine 3 H- epibatidine Smoking and chronic nicotine upregulate nicotine binding

14. Once activated, nicotinic receptors :  Close and open again  Desensitize (remain closed for minutes to hours)  Inactivate (remain closed until degraded inside the cell) Inactivation may contribute to ongoing smoking behavior.

15. How do current smoking cessation therapies work?

16. Nicotine Patch:  Replaces the nicotine from cigarettes, but has a much slower and longer- lasting kinetic profile  Likely desensitizes and inactivates nicotinic receptors  Adding the nicotinic antagonist mecamylamine to the patch may result in stronger receptor inhibition

17. Nicotine Vaccine:  Can bind nicotine as it gets into the blood stream and remove it from the system  Would be ideal for preventing relapse as a result of brief cigarette exposure  Might be useful for preventing smoking initiation in a high risk population  Could potentially increase smoking if administered before a quit attempt

18. Bupropion (Zyban):  Acts like a dopamine agonist (prevents DA reuptake)  Can block nicotinic receptors  Has antidepressant properties that may also facilitate quitting  Other actions?

19. On beyond nicotine: How can we use what we know to develop better therapies for smoking cessation?

20. Development of specific nicotinic receptor subtype agonists and antagonists -  6/  3 subunits are primarily on dopamine neurons -  7 subunits may be critical for modulating dopamine drive over time

21. Targeting signaling pathways related to nicotinic receptor activity - compounds that reverse the plasticity related to repeated nicotine use may be useful adjuncts to behavioral interventions - modulation of glutamate and GABA pathways may strongly affect smoking behavior