While an extensive literature supports the notion that mesocorticolimbic dopamine plays a role in negative reinforcement, recent evidence suggests that dopamine exclusively encodes the value of positive reinforcement. In the present study, we employed a behavioral economics approach to investigate whether dopamine plays a role in the valuation of negative reinforcement. Using rats as subjects, we first applied fast-scan cyclic voltammetry (FSCV) to determine that dopamine concentration decreases with the number of lever presses required to avoid electrical footshock (i.e., the economic price of avoidance). Analysis of the rate of decay of avoidance demand curves, which depict an inverse relationship between avoidance and increasing price, allows for inference of the worth an animal places on avoidance outcomes. Rapidly decaying demand curves indicate increased price sensitivity, or low worth placed on avoidance outcomes, while slow rates of decay indicate reduced price sensitivity, or greater worth placed on avoidance outcomes. We therefore used optogenetics to assess how inducing dopamine release causally modifies the demand to avoid electrical footshock in an economic setting. Increasing release at an avoidance predictive cue made animals more sensitive to price, consistent with a negative reward prediction error (i.e., the animal perceives they received a worse outcome than expected). Increasing release at avoidance made animals less sensitive to price, consistent with a positive reward prediction error (i.e., the animal perceives they received a better outcome than expected). These data demonstrate that transient dopamine release events represent the value of avoidance outcomes and can predictably modify the demand to avoid.

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The rewarding and reinforcing effects of abused drugs are thought to be mediated by their ability to increase brain dopamine levels. The canon holds that all drugs of abuse increase dopamine release in a brain region called the nucleus accumbens (NAc) but, due to the temporal constraints of previously available neurochemical techniques, it remains unknown how distinct drugs of abuse alter dopamine release in real time. A real time assessment is important due to the nature by which dopamine neurons fire. In awake and behaving rats, dopamine neurons fire in two distinct patterns. At ‘rest,’ dopamine neurons fire in a low‐frequency pacemaker fashion that is thought to produce a tone on high‐affinity dopamine receptors in the NAc. When presented with motivationally relevant stimuli, dopamine neurons fire in high‐frequency bursts. The phasic bursts of dopamine neural activity contribute to the generation of subsecond release events in the NAc that are sufficient in concentration to occupy low‐affinity dopamine receptors. As the activation of these low‐affinity receptors is thought to be particularly important in strengthening action‐outcome associations, we are especially interested in investigating how drugs of abuse alter their patterns of release. Fast‐scan cyclic voltammetry (FSCV) allows for the detection of dopamine release events with a temporal resolution of milliseconds, making it an ideal tool with which to examine how drugs of abuse alter transient dopamine release events in real time. We obtain two primary dependent measures of dopamine release, the frequency at which they occur and the total concentration of each event.Here, we are using FSCV to compare how different drugs of abuse alter the frequency and amplitude of dopamine release events in the awake and behaving rat. Drugs of investigation include: ethanol, diazepam, zolpidem, WIN55,212‐2, methamphetamine, methylenedioxymethamphetamine (MDMA) and heroin. Preliminary data show that the sedative‐hypnotics ethanol, diazepam and zolpidem all increase the frequency but decrease the amplitude of dopamine release events; although the ethanol amplitude effect is biphasic. Heroin, the synthetic cannabinoid WIN55,212‐2, and the psychostimulant methamphetamine increase both the frequency and amplitude of dopamine release events. The psychostimulant and tryptamine psychedelic MDMA increases the amplitude of dopamine release events but not their frequency. Together, these data reveal that the effects of abused drugs on transient dopamine release events varies across drug classes.Support or Funding InformationFunding for this work was provided by NSF grant IOS‐1557755, NIH grant R03DA038734, Boettcher Young Investigator Award and NARSAD Young Investigator Award to EBOThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.