regina m. carelli associate professor department of psychology the university of north carolina,...
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Regina M. CarelliAssociate Professor
Department of PsychologyThe University of North Carolina, Chapel Hill
Rapid Dopamine Signaling:Cocaine Versus “Natural” Rewards
Paxinos & Watson (1998)
Nucleus accumbens
Prefrontal cortex
Hippocampus
Basolateral Amygdala
Ventral Tegmental Area
Glutamate
Dopamine
Brain “Reward” Circuit
To address this issue:
Measure chemical changes on a time scale that can resolve the precise relationship between dopamine release and individual behavioral events.
The Nucleus Accumbens and Reward
Question: What is the role of dopamine in reward?
NH2
OH
OH
Dopamine
NH2
O
O
+2H+
Dopamine-o-quinone
- 2e -
+ 2e -
10 ms(400 V/s)
0
+1400 mV
-600 mV
vsAg/AgCl
Eapp
every 100 ms
Iout
10 ms
Electrochemical Detection of Dopamine: FSCV
Voltammetric Measurement of Dopamineduring 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
Cocaine Self-Administration Task
Session Begins:Cuelight On
Lever Press(FR1)
I.V. CocaineInfusion(0.33 mg/inf)
Tone-HouselightStimulus
-10 -5 R 5 10 15 20 sec
Inter-infusion Interval
Phasic Changes in Dopamine Relative to Lever Press Responding
for Intravenous Cocaine?
Phillips et al., Nature, 422, 614-618, 2003
Phasic Dopamine at Lever Press
-10 -5 R 5 10SEC
50 nM
Across All Animals (n=6)
-10 -5 R 5 10
50 nM
LeverApproach
Dopamine Response toCocaine-Associated Cue?
50 nM
Tone-Houselight Stimulus (20 s)
-5 S 5 10SEC
50 nM
*Cocaine Self-Administration History
-5 S 5 10SEC
-5 S 5 10SEC
No Cocaine Self-Administration
50 nM
*Cocaine Self-Administration History
-5 S 5 10SEC
Rapid Dopamine Signaling: Represents a Learned Association
Extinction/Reinstatement Experiment
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
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 sec0
10
20
30
40
50le
ver-
resp
onse
Extinction/Reinstatement: Behavior
Maintenance Extinction Reinstatement
Saline
Prime
5 10 15 20 25 30 35 40 450
50
100
150
Maintenance Extinction Reinstatement
DA
con
cent
ratio
n (n
M)
Extinction/Reinstatement
‘Prime’
Rapid Dopamine Signaling is Attenuated during Extinction
Maintenance Extinction Reinstatement0
50
100
150
ns
**
[DA
] (nM
)
Rapid Dopamine Signaling
Goal-Directed Behaviors for “Natural” Rewards
Sucrose Reinforcement Task
Session Begins:Cuelight On/Lever Extension
Lever Press(FR1)
IntraoralSucrose0.3 M
Tone-HouselightStimulus
-10 -5 R 5 10 15 20 sec
30-60 sec ITI
Phasic Changes in Dopamine during Goal-Directed Behaviorsfor ‘Natural’ (Sucrose) Reward?
25 nM
Dopamine Signal: Cue Light On/Lever Extension
-12 -6 R 6 12
Cue Light On/Lever Extension
Dopamine Response toCue Light On/Lever Extension?
-5 C 5 10SEC
Trained Rats (Cue-light On/Lever Extension)
25 nM
-5 C 5 10SEC
25 nM
-5 C 5 10SEC
Naive Rats (No Cue-Sucrose pairings)
Trained Rats (Cue-light On/Lever Extension)
Short versus Long Latency Trials
-10 -5 R 5 10
25 nM
Short Latency Response to Cue Onset/Lever Extension
-10 -5 R 5 10
25 nM
0.1 - 133.4 s
Long Latency Response to Cue Onset/Lever Extension
Cue Press
150
100
50
0
*
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)
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
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)
Acknowledgements
R. Mark WightmanUNC Chem. Electronics Shop
NIH/NIDA