Here, we demonstrate that taste stimuli signaling delayed cocaine availability can induce a negative affective state that alters hedonic sensitivity, brain reward processing, and motivated behavior. We observed the emergence of negative affect and reduced dopamine release using taste cues that signaled delayed cocaine availability when presented prior to cocaine self-administration. Later, in the same session, dopamine release was enhanced to cues that signaled imminent cocaine delivery during self-administration. It should be noted that some associations (like those with visceral malaise) are more readily formed with the sensory modality of taste, rather than vision or hearing (38
). However, in this report we demonstrate that a taste cue can either elevate or diminish dopamine release depending on its temporal relationship to the availability of cocaine. This finding is consistent with previous reports demonstrating that close temporal pairings of intraoral sucrose or saccharin delivery with cocaine are not sufficient to produce overt signs of aversion (15
). The fact that reduced dopamine release and behavioral aversion were observed in response to the ‘delay,’ but not the ‘immediate’ taste cue suggests that the mechanism of learning across these temporal periods is fundamentally different and motivationally relevant. Ultimately, the conditioning observed here exerted a broad impact on behavior, not only altering affect, but also dopamine release and sensitivity to brain stimulation reward.
These findings complement a large literature indicating that the shell subregion of the NAc has an important role in processing the primary motivating properties of rewarding and aversive stimuli (32
). Psychostimulants preferentially induce dopamine release in the shell (31
) and animals will self-administer dopamine agonists directly to into this region (42
). Pharmacological inhibition of the shell increases motivated behavior (43
) and hedonic responses to taste stimuli (44
). Of course, reward and aversion processing in the NAc is plastic, as environmental conditions may flexibly dictate the current role of the nucleus in processing appetitive or aversive stimuli (21
). Consistent with these findings, we observe that dopamine release in this region, but not the core subregion, is rapidly elevated by palatable, and reduced by unpalatable, taste stimuli. Further we show that these rapid fluctuations in release can be altered by devaluation from learned associations, specifically the predictive and temporal relationship of the taste cue to cocaine availability.
Together, the observed alteration in affect, dopaminergic function, and reward processing suggests that conditioned negative affect may influence motivated behavior, perhaps through negative reinforcement as postulated by others (7
). That is, drug-seeking may result as an effort to alleviate negative mood, particularly in a situation in which the cue signals that cocaine is not immediately available. This may be analogous to a human cocaine user being shown a drug-predictive cue in the absence of the drug, a design that elicits craving and negative mood (48
). Although cocaine use has negative physiological consequences (11
) it is unclear how these consequences, which abate hours or days after drug cessation (7
), continue to promote drug-seeking. Cue-induced dampening of dopamine release and reduced sensitivity to brain stimulation reward shown in this report present a potential mechanism. The previously-reported predictive relationship between the aversion expressed for a taste cue and subsequent cocaine intake supports this possibility. That is, a cocaine predictive taste cue elicits the behavioral expression of aversion, changes in neuronal firing rates (13
), and shown here, reduced dopamine release in the NAc, a brain area critical for the proper expression of motivated behavior. These findings are consistent with the hypothesis that drug-predictive cues can elicit conditioned compensatory responses in opposition to the effects of the drug (50
). If a negative affective state can be elicited by a cocaine-predictive cue, then negative reinforcement mechanisms may promote drug-seeking, as predicted by some addiction theories (7
However, we also observed rapid and pronounced dopamine release during cocaine self-administration and for cues (either tastants or audiovisual) that have been paired with immediate cocaine delivery. In this way, the data also are consistent with the interpretation that enhanced dopaminergic responses to drug-predictive stimuli (that signal imminent drug delivery) reflect incentive and promote drug-seeking (4
). In this design, reduced incentive may be present in a ‘delayed drug’ context, but critically, may be quickly reversed by cues that predict ‘immediate drug’ availability. Together, our findings illustrate a rapidly dynamic reward processing system that can switch from dampened to enhanced functionality depending on the specific drug-predictive environment of the animal.