1. Rapid Dopamine Signaling: Cocaine Versus “Natural” Rewards
Regina M. Carelli
Associate Professor
Department of Psychology
The University of North Carolina, Chapel Hill

2. Ventral Tegmental Area
Brain “Reward” Circuit
Glutamate
Dopamine
Hippocampus
Prefrontal cortex
Ventral Tegmental Area
Basolateral Amygdala
Nucleus accumbens
Paxinos & Watson (1998)

3. The Nucleus Accumbens and Reward Question:
What is the role of dopamine in reward?
To address this issue:
Measure chemical changes on a time scale that can
resolve the precise relationship between dopamine
release and individual behavioral events.

4. Electrochemical Detection of Dopamine: FSCV
+1400 mV vs
Ag/AgCl
every 100 ms
Eapp
-600 mV
10 ms
(400 V/s)
- 2e- OH
Iout
Dopamine OH O
NH2 O
+ 2e-
10 ms
Dopamine-o-quinone
+2H+
NH2

5. Voltammetric Measurement of Dopamine
during Cocaine Self-Administration
Train rats to self-administer cocaine
Surgical preparation for voltammetry
Carbon fiber electrode is lowered in micromanipulator into accumbens
Measure phasic changes in DA (on subsecond timescale) during self-administration

6. Cocaine Self-Administration Task
Session Begins:
Cuelight On
Lever Press
(FR1)
I.V. Cocaine
Infusion
(0.33 mg/inf)
Inter-infusion Interval
Tone-Houselight
Stimulus
-10 -5 R 5 10 15 20
sec

7. Phasic Changes in Dopamine Relative to Lever Press Responding
for Intravenous Cocaine?

8. Dopamine at Lever Press
Phasic
Dopamine at Lever Press - 10 5 R
SEC 50 nM
Phillips et al., Nature, 422, , 2003

9. Across All Animals (n=6)
50 nM
Lever
Approach
-10 -5 R 5 10

10. Cocaine-Associated Cue?
Dopamine Response to
Cocaine-Associated Cue?

11. Tone -
Houselight
Stimulus (20 s)
50 nM - 5 S 5
SEC 10

12. Cocaine Self-Administration History*
50 nM -5 S 5
SEC 10

13. Cocaine Self-Administration History No Cocaine Self-Administration*
50 nM -5 S 5
SEC 10
No Cocaine Self-Administration -5 S 5
SEC 10

14. Rapid Dopamine Signaling: Represents a Learned Association
Extinction/Reinstatement Experiment

15. Extinction/Reinstatement Experiment
1) Maintenance: Lever press for cocaine (0.33 mg/inf; FR1)
2) Extinction: Cocaine was replaced with saline.
3) Reinstatement: After 30 min of no responding, the saline was replaced
with cocaine. Behavior was reestablished by giving a ‘priming’ infusion of cocaine paired with the stimulus

16. Extinction/Reinstatement: Behavior50
Prime 40 30
lever-response
Saline 20 10
1000
2000
3000
4000
5000
6000
7000
8000
9000
sec
Maintenance
Extinction
Reinstatement

17. Extinction/Reinstatement
150
‘Prime’
100
DA concentration (nM) 50 5 10 15 20 25 30 35 40 45
Maintenance
Extinction
Reinstatement

18. Rapid Dopamine Signaling is Attenuated during Extinctionns * *
150
100
[DA] (nM) 50
Maintenance
Extinction
Reinstatement

19. Rapid Dopamine Signaling
Goal-Directed Behaviors for “Natural” Rewards

20. Sucrose Reinforcement Task
Session Begins:
Cuelight On/
Lever Extension
Lever Press
(FR1)
Intraoral
Sucrose
0.3 M
30-60 sec ITI
Tone-Houselight
Stimulus
-10 -5 R 5 10 15 20
sec

21. Phasic Changes in Dopamine during Goal-Directed Behaviors
for ‘Natural’ (Sucrose) Reward?

22. Dopamine Signal: Cue Light On/Lever Extension
25 nM
Cue Light On/
Lever Extension
-12 -6 R 6 12

23. Cue Light On/Lever Extension?
Dopamine Response to
Cue Light On/Lever Extension?

24. Trained Rats (Cue-light On/Lever Extension)5 C 10
SEC
25 nM

25. Naive Rats (No Cue-Sucrose pairings)
Trained Rats (Cue-light On/Lever Extension) - 5 C 10
SEC
25 nM
Naive Rats (No Cue-Sucrose pairings) - 5 C 10
SEC

26. Short versus Long Latency Trials

27. Short Latency Response to Cue Onset/Lever Extension
25 nM
-10 -5 R 5 10

28. Long Latency Response to Cue Onset/Lever Extension*
150
100 50
25 nM
[Dopamine] (nM)
Cue
Press s
-10 -5 R 5 10

29. Summary: Rapid DA Signaling
Similarities - Increases in DA:
- Before operant response (cocaine or sucrose)
- Relative to cues (cocaine or sucrose)
- Reflect learned associations (cocaine or sucrose)

30. Summary: Rapid DA Signaling
Similarities - Increases in DA:
- Before operant response (cocaine or sucrose)
- Relative to cues (cocaine or sucrose)
- Reflect learned associations (cocaine or sucrose)
Differences - Temporal profile of DA transients
- Reflect fundamental difference between ‘natural’
vs. drug rewards?
- Or, more likely, predictive strength of the cues
signaling reinforcer delivery

31. Summary: Rapid DA Signaling
Similarities - Increases in DA:
- Before operant response (cocaine or sucrose)
- Relative to cues (cocaine or sucrose)
- Reflect learned associations (cocaine or sucrose)
Differences - Temporal profile of DA transients
- Reflect fundamental difference between ‘natural’
vs. drug rewards?
- Or, more likely, predictive strength of the cues
signaling reinforcer delivery
Implication: Rapid dopamine signaling appears to promote goal- directed behaviors irrespective of reinforcer type (cocaine or ‘natural’ reward)

32. Acknowledgements
R. Mark Wightman
NIH/NIDA
UNC Chem. Electronics Shop