a dual role for nicotine in reinforcement: the interaction between nicotine and non-drug cues (what...

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 NeuroscienceUniversity of Pittsburgh

Will pressfor

nicotine

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

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

• 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?

Nonpharmacological stimuli DOimpact nicotine reinforcement in rats

Nicotine and nonpharmacological stimuliinteract 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

FR 1 FR 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

Nicotine - 0.03 mg/kg/inf

Day

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Response on Active Lever20

40

60

80

100

120

140

160

180

200

FR 1 FR 2 FR 5

Contingent nicotine + VS

Acquisition of NIC-SA with or without VS


Day

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23


40

60

80

100

120

140

160

180

200

FR 1 FR 2 FR 5


Contingent Saline + VS

Contingent Saline + no VS



Day

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23


40

60

80

100

120

140

160

180

200

FR 1 FR 2 FR 5


Contingent Saline + no VS

Contingent nicotine + no VSContingent Saline + VS



Day

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23


40

60

80

100

120

140

160

180

200

FR 1 FR 2 FR 5


Contingent nicotine + no VSContingent Saline + VS

Nicotine + VS - additive


Acquisition of NIC-SA without VS: dose-response

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

• 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)?

NIC

Impact of contingency on reinforced behavior

Will press for

NIC +

VS Will pressForVS

Impact of noncontingent NIC on responding for the VS

Donny EC, Chaudhri N & Caggiula AR et al. (2003) Psychopharmacology

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 experimentsHumans: Sight, smell, taste of cigarette smoke and other stimuli in environment while smoking.

Impact of noncontingent NIC : dose-response

Session

Number of Reinforcers2

4

6

8

10

12

14

16

18

20

22 0.01 mg/kg/inf 0.03 mg/kg/inf 0.09 mg/kg/inf

FR5 FR5 FR59 11 13 15 1710 12 14 16 9 11 13 15 1710 12 14 16 9 11 13 15 1710 12 14 16

Noncontingent NIC + VSSaline + VS

Contingent NIC + VS

Session

Number of Reinforcers1

2

3

4

5

6

7

8

9

10 0.01 mg/kg/inf 0.03 mg/kg/inf 0.09 mg/kg/inf

Noncontingent NIC + VSSaline + VS

Contingent NIC + VS

PR PR PR1819 20 2122 2324 25 26 27 28 29 1819 20 2122 2324 25 26 27 28 29 1819 20 2122 2324 25 26 27 28 29

Impact of noncontingent NIC on a PR schedule

Does noncontingent nicotine enhance the salience of all nonpharmacological stimuli equally?

STIMULUS = 5 second tone onset and 5 second house light offset

Group 1 - PAIREDSucrose (60)

Stimulus (30)

Pavlovian conditioningDays 1-14; levers retracted

Group 2 - UNPAIREDSucrose (60)

Stimulus (30)

30 min

Pavlovian-to-Instrumental Transfer (Test-day) Day 15; levers extended; no sucrose; 30-min from 1st press

Self-administration sessions (FR and PR)

PAIRED UNPAIREDSaline + CR Saline + CRContingent NIC + CR Contingent NIC + CR Noncontingent NIC + CR Noncontingent NIC + CR

10

20

30

40

50 PAIRED (n=50)

Active lever Inactive Lever Stimulus CR (p)

Test-day

Paired

10

20

30

40

50 UNPAIRED (n=32)

Active lever Inactive Lever StimulusCR (un-p)

Unpaired

Session

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Number of Reinforcements5

10

15

20

25

30

35

40

45

Noncontingent SAL + CR (p) Noncontingent SAL + CR (un-p)

FR1 FR2 FR5 FR1

Impact of noncontingent NIC on a differentially reinforcing, nonpharmacological stimulus

Session

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24


10

15

20

25

30

35

40

45

Contingent NIC + CR (p)Noncontingent SAL + CR (p)

FR1 FR2 FR5 FR1


Paired Stimulus

Session

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24


10

15

20

25

30

35

40

45

Contingent NIC + CR (p)Noncontingent NIC + CR (p) Noncontingent SAL + CR (p)

FR1 FR2 FR5 FR1


Paired Stimulus

Session

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24


10

15

20

25

30

35

40

45

Contingent NIC + CR (un-p) Noncontingent SAL + CR (un-p)

FR1 FR2 FR5 FR1


Unpaired Stimulus

Session

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24


10

15

20

25

30

35

40

45

Contingent NIC + CR (un-p) Noncontingent NIC + CR (un-p) Noncontingent SAL + CR (un-p)

FR1 FR2 FR5 FR1


Unpaired Stimulus


Session

25 26 27


2

3

4

5

6

7

8

9

10

11

12

13

Noncontingent SAL + CR (p)

Noncontingent SAL + CR (un-p)

Progressive Ratio Schedule


Session

25 26 27


2

3

4

5

6

7

8

9

10

11

12

13

Contingent NIC + CR (p)

Noncontingent NIC + CR (p)

Noncontingent SAL + CR (p)


Paired Stimulus


Session

25 26 27


2

3

4

5

6

7

8

9

10

11

12

13

Contingent NIC + CR (un-p)



Unpaired Stimulus


Session

25 26 27


2

3

4

5

6

7

8

9

10

11

12

13

Contingent NIC + CR (un-p)

Noncontingent NIC + CR (un-p)



Unpaired Stimulus


Contingency by Pairing Interaction p <0.05

Reinforcements

(last 2 days of PR)

6

7

8

9

10

11

12

Contingent NIC + CR

Noncontingent NIC + CR

Paired Unpaired

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

““People smoke to receive nicotine”People smoke to receive nicotine”Primary Reinforcer: Behaviors that lead to nicotine delivery are strengthened

““Nicotine makes people smokeNicotine 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?

Caggiula Lab

Tony CaggiulaAlan SvedEric DonnyMatt PalmatierXiu Liu

Sheri BoothMaysa GharibLaure Craven

Prema ChaudharyDonna PacelliCaroline BourisShannon Allen

Peter Olausson

NIDAHHMI

a dual role for nicotine in reinforcement: the interaction between nicotine and non-drug cues (what...

Documents

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nic vs

rats nicotine

properties of nicotine

nicotine addiction

impact nicotine reinforcement

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