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

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

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.

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

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

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

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

Dopamine at Lever Press Phasic Dopamine at Lever Press - 10 5 R SEC 50 nM Phillips et al., Nature, 422, 614-618, 2003

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

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

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

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

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

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

Extinction/Reinstatement: Behavior 50 Prime 40 30 lever-response Saline 20 10 1000 2000 3000 4000 5000 6000 7000 8000 9000 sec Maintenance Extinction Reinstatement

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

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

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

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

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

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

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

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

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

Short versus Long Latency Trials

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

Long Latency Response to Cue Onset/Lever Extension * 150 100 50 25 nM [Dopamine] (nM) Cue Press 0.1 - 133.4 s -10 -5 R 5 10

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 Wightman NIH/NIDA UNC Chem. Electronics Shop