1. A dual role for nicotine in reinforcement: the interaction between nicotine and non-drug cues (What can a lab rat tell us about why people smoke?) Nadia Chaudhri Center for Neuroscience University of Pittsburgh Will press for nicotine

2. Why do people smoke? “nicotine is the drug in tobacco that causes addiction” Health Consequences of Smoking: Nicotine Addiction. A report by the Surgeon General, USDHHS, 1988

3. Nonpharmacological factors Smoking cigarettes is more rewarding than isolated nicotine delivery De-nicotinized cigarettes reduce craving and withdrawal Sensory stimuli, such as visual and olfactory cues associated with smoke are reinforcing

4. Smoking cigarettes is more rewarding than isolated nicotine delivery Nonpharmacological factors De-nicotinized cigarettes reduce craving and withdrawal Sensory stimuli, such as visual and olfactory cues associated with smoke are reinforcing Do nonpharmacological stimuli impact nicotine self-administration in rats?

5. Nonpharmacological stimuli DO impact nicotine reinforcement in rats Nicotine and nonpharmacological stimuli interact synergistically to result in high levels of operant behavior Dual-reinforcing properties of nicotine: Relatively weak, primary reinforcer Enhance the reinforcing properties of behaviorally relevant, nonpharmacological environmental stimuli Donny EC, Chaudhri N & Caggiula AR et al. (2003) Psychopharmacology

6. FR 1FR 5FR 2 Fixed-ratio Reinforcement Schedule (60 min) Responses : 3, 6, 10, 15, 20, 25, 32, 40 … Infusion # 1, 2, 3, 4, 5, 6, 7, 8 … Progressive Ratio Reinforcement Schedule (4 hours) Signals Cue Light House Light Infusion Nic Delivery (on) Nic + (off) Nic - Compound Visual Stimulus Male, Sprague Dawley rats Reversed light/dark cycle 20 g food per day Prior food training Nicotine self-administration in rats

7. Contingent nicotine + VS Acquisition of NIC-SA with or without VS

8. Contingent nicotine + VS Contingent Saline + VS Contingent Saline + no VS Acquisition of NIC-SA with or without VS

9. Contingent nicotine + VS Contingent Saline + no VS Contingent nicotine + no VS Contingent Saline + VS Acquisition of NIC-SA with or without VS

10. Contingent nicotine + VS Contingent nicotine + no VS Contingent Saline + VS Nicotine + VS - additive Acquisition of NIC-SA with or without VS

11. Acquisition of NIC-SA without VS: dose-response

12. Interim summary 1.Nicotine does function as a primary reinforcer, although this effect is relatively weak in the absence of a nonpharmacological stimulus 2. Nicotine interacts synergistically with non-drug stimuli to promote stable, high levels of operant behavior 3.Like nicotine, the VS we use is also a weak primary reinforcer

13. How does such a powerfully addictive behavior, smoking, emerge from such a weak primary reinforcer, nicotine? Smoking paradox Is nicotine functioning as more than just a primary reinforcer? How can a weak primary reinforcer, nicotine, synergize with environmental stimuli to produce high rates of self-administration in rats (and smoking in people)?

14. NIC Impact of contingency on reinforced behavior Will press for NIC + VS Will press For VS

15. Impact of noncontingent NIC on responding for the VS Donny EC, Chaudhri N & Caggiula AR et al. (2003) Psychopharmacology

16. Impact of noncontingent NIC on responding for the VS Donny EC, Chaudhri N & Caggiula AR et al. (2003) Psychopharmacology

17. Interim summary 1)Is noncontingent nicotine as effective at enhancing the reinforcing value of the VS across a range of doses, and does it impact motivation to obtain the VS when assessed using a progressive ratio reinforcement schedule? 2) Does noncontingent nicotine enhance the salience of all nonpharmacological stimuli equally? Nicotine, delivered noncontingently, elevated responding for a weakly reinforcing, nonpharmacological stimulus, suggesting that nicotine can enhance the reinforcing properties of: Rats: Environmental stimuli in self-administration experiments Humans: Sight, smell, taste of cigarette smoke and other stimuli in environment while smoking.

18. Impact of noncontingent NIC : dose-response

21. Impact of noncontingent NIC on a PR schedule

23. Does noncontingent nicotine enhance the salience of all nonpharmacological stimuli equally? STIMULUS = 5 second tone onset and 5 second house light offset Group 1 - PAIRED Sucrose (60) Stimulus (30) Pavlovian conditioning Days 1-14; levers retracted Group 2 - UNPAIRED Sucrose (60) Stimulus (30) 30 min Pavlovian-to-Instrumental Transfer (Test-day) Day 15; levers extended; no sucrose; 30-min from 1 st press Self-administration sessions (FR and PR) PAIRED UNPAIRED Saline + CR Contingent NIC + CR Contingent NIC + CR Noncontingent NIC + CR Noncontingent NIC + CR Test-day Paired Unpaired

24. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus

25. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus Paired Stimulus

26. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus Paired Stimulus

27. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus Unpaired Stimulus

28. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus Unpaired Stimulus

29. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus

30. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus Paired Stimulus

31. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus Unpaired Stimulus

32. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus Unpaired Stimulus

33. Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus

34. Interim summary 1.The reinforcement-enhancing effects of nicotine are not specific to one type of nonpharmacological stimulus, the VS 2.The ability of nicotine to enhance the reinforcing properties of a nonpharmacological stimulus depends on the reinforcing value of that stimulus 3.Like self-administered nicotine, response-independent nicotine delivery can increase motivation to obtain nonpharmacological stimuli, as tested with a progressive ratio schedule

35. “People smoke to receive nicotine” Primary Reinforcer: Behaviors that lead to nicotine delivery are strengthened “Nicotine makes people smoke “Nicotine makes people smoke” Reinforcement-Enhancing: Nicotine can amplify or enhance the motivational/reinforcing properties of other stimuli by a mechanism that is not dependent on a predictable temporal (contingent) association with either the stimuli or the behavior Why do people smoke?

36. Caggiula Lab Tony Caggiula Alan Sved Eric Donny Matt Palmatier Xiu Liu Sheri Booth Maysa Gharib Laure Craven Prema Chaudhary Donna Pacelli Caroline Bouris Shannon Allen Peter Olausson NIDA HHMI