Benjamin T. Saunders

The role of dopamine in the accumbens core in the expression of pavlovian-conditioned responses

The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction‐error signal necessary for stimulus–reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value (‘incentive salience’) to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of Pavlovian‐conditioned approach behavior – one in which the cue acquires powerful motivational properties (sign‐tracking) and another closely related one in which it does not (goal‐tracking). After acquisition of these conditioned responses (CRs), intra‐accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign‐tracking CR, but not a goal‐tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction‐like decline in behavior, but maximally impaired expression of a sign‐tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction‐error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus–reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties.

A cocaine cue acts as an incentive stimulus in some but not others: implications for addiction.

BACKGROUND In addicts drug cues attract attention, elicit approach, and motivate drug-seeking and drug-taking behavior, and addicts find it difficult to resist such cues. In preclinical studies we have found, however, that food cues acquire incentive motivational properties only in a subset of individuals. For example, a food cue becomes attractive, eliciting approach and engagement with it, and acts as an effective conditional reinforcer in some rats but not others. We asked, therefore, whether rats that have a propensity to attribute incentive salience to a food cue are the same ones that attribute incentive value to a drug (cocaine) cue. METHODS We first used a Pavlovian conditioned approach procedure to determine which individual rats attributed incentive salience to a food cue. A second cue was then associated with the IV self-administration of cocaine. Later, the ability of the cocaine cue to maintain self-administration behavior and to reinstate self-administration after extinction was assessed. RESULTS We report that in individuals that had a propensity to attribute incentive salience to a food cue, a cocaine cue spurred motivation to take drugs (its removal greatly diminished self-administration) and reinstated robust drug-seeking after extinction. However, in those individuals that failed to attribute incentive salience to a food cue, the cocaine cue was relatively devoid of incentive motivational properties. CONCLUSIONS We conclude that it is possible to determine, before any drug experience, which individuals will most likely have difficulty resisting drug cues, a trait that might confer susceptibility to addiction.

Quantifying Individual Variation in the Propensity to Attribute Incentive Salience to Reward Cues

If reward-associated cues acquire the properties of incentive stimuli they can come to powerfully control behavior, and potentially promote maladaptive behavior. Pavlovian incentive stimuli are defined as stimuli that have three fundamental properties: they are attractive, they are themselves desired, and they can spur instrumental actions. We have found, however, that there is considerable individual variation in the extent to which animals attribute Pavlovian incentive motivational properties (“incentive salience”) to reward cues. The purpose of this paper was to develop criteria for identifying and classifying individuals based on their propensity to attribute incentive salience to reward cues. To do this, we conducted a meta-analysis of a large sample of rats (N = 1,878) subjected to a classic Pavlovian conditioning procedure. We then used the propensity of animals to approach a cue predictive of reward (one index of the extent to which the cue was attributed with incentive salience), to characterize two behavioral phenotypes in this population: animals that approached the cue (“sign-trackers”) vs. others that approached the location of reward delivery (“goal-trackers”). This variation in Pavlovian approach behavior predicted other behavioral indices of the propensity to attribute incentive salience to reward cues. Thus, the procedures reported here should be useful for making comparisons across studies and for assessing individual variation in incentive salience attribution in small samples of the population, or even for classifying single animals.

Individual Variation in the Motivational Properties of Cocaine

Cues in the environment associated with drug use draw the attention of addicts, elicit approach, and motivate drug-seeking and drug-taking behavior, making abstinence difficult. However, preclinical studies have identified large individual differences in the extent to which reward cues acquire these incentive motivational properties. For example, only in some rats does a spatially discrete food cue become attractive, eliciting approach and engagement with it, and acts as an effective conditioned reinforcer. Moreover, a discrete cocaine cue also acquires greater motivational control over behavior in rats prone to attribute incentive salience to a food cue. In this study, we asked whether there is similar individual variation in the extent to which interoceptive cues produced by cocaine itself instigate cocaine-seeking behavior. After quantifying individual variation in the propensity to attribute incentive salience to a food cue, rats were trained to self-administer cocaine in the absence of an explicit conditional stimulus. We then assessed motivation for cocaine by: (1) performance on a progressive ratio schedule, and (2) the degree to which a cocaine ‘prime’ reinstated cocaine-seeking following extinction of self-administration behavior. We found that rats prone to attribute incentive salience to a food cue worked harder for cocaine, and showed more robust cocaine-induced reinstatement. We conclude that there is considerable individual variation in the motivational properties of cocaine itself, and this can be predicted by the propensity to attribute incentive salience to reward cues.

Aversive stimuli differentially modulate real-time dopamine transmission dynamics within the nucleus accumbens core and shell

Although fear directs adaptive behavioral responses, how aversive cues recruit motivational neural circuitry is poorly understood. Specifically, while it is known that dopamine (DA) transmission within the nucleus accumbens (NAc) is imperative for mediating appetitive motivated behaviors, its role in aversive behavior is controversial. It has been proposed that divergent phasic DA transmission following aversive events may correspond to segregated mesolimbic dopamine pathways; however, this prediction has never been tested. Here, we used fast-scan cyclic voltammetry to examine real-time DA transmission within NAc core and shell projection systems in response to a fear-evoking cue. In male Sprague Dawley rats, we first demonstrate that a fear cue results in decreased DA transmission within the NAc core, but increased transmission within the NAc shell. We examined whether these changes in DA transmission could be attributed to modulation of phasic transmission evoked by cue presentation. We found that cue presentation decreased the probability of phasic DA release in the core, while the same cue enhanced the amplitude of release events in the NAc shell. We further characterized the relationship between freezing and both changes in DA as well as local pH. Although we found that both analytes were significantly correlated with freezing in the NAc across the session, changes in DA were not strictly associated with freezing while basic pH shifts in the core more consistently followed behavioral expression. Together, these results provide the first real-time neurochemical evidence that aversive cues differentially modulate distinct DA projection systems.

Cue-Evoked Cocaine “Craving”: Role of Dopamine in the Accumbens Core

Drug-associated cues can acquire powerful motivational control over the behavior of addicts, and can contribute to relapse via multiple, dissociable mechanisms. Most preclinical models of relapse focus on only one of these mechanisms: the ability of drug cues to reinforce drug-seeking actions following a period of extinction training. However, in addicts, drug cues typically do not follow seeking actions; they precede them. They often produce relapse by evoking a conditioned motivational state (“wanting” or “craving”) that instigates and/or invigorates drug-seeking behavior. Here we used a conflict-based relapse model to ask whether individual variation in the propensity to attribute incentive salience to reward cues predicts variation in the ability of a cocaine cue to produce conditioned motivation (craving) for cocaine. Following self-administration training, responding was curtailed by requiring rats to cross an electrified floor to take cocaine. The subsequent response-independent presentation of a cocaine-associated cue was sufficient to reinstate drug-seeking behavior, despite the continued presence of the adverse consequence. Importantly, there were large individual differences in the motivational properties of the cocaine cue, which were predicted by variation in the propensity to attribute incentive salience to a food cue. Finally, a dopamine antagonist injected into the nucleus accumbens core attenuated, and amphetamine facilitated, cue-evoked cocaine seeking, implicating dopamine signaling in cocaine cue-evoked craving. These data provide a promising preclinical approach for studying sources of individual variation in susceptibility to relapse due to conditioned craving and implicate mesolimbic dopamine in this process.

Variation in the form of Pavlovian conditioned approach behavior among outbred male Sprague-Dawley rats from different vendors and colonies: sign-tracking vs. goal-tracking.

Even when trained under exactly the same conditions outbred male Sprague-Dawley (SD) rats vary in the form of the Pavlovian conditioned approach response (CR) they acquire. The form of the CR (i.e. sign-tracking vs. goal-tracking) predicts to what degree individuals attribute incentive salience to cues associated with food or drugs. However, we have noticed variation in the incidence of these two phenotypes in rats obtained from different vendors. In this study, we quantified sign- and goal-tracking behavior in a reasonably large sample of SD rats obtained from two vendors (Harlan or Charles River), as well as from individual colonies operated by both vendors. Our sample of rats acquired from Harlan had, on average, more sign-trackers than goal-trackers, and vice versa for our sample of rats acquired from Charles River. Furthermore, there were significant differences among colonies of the same vendor. Although it is impossible to rule out environmental variables, SD rats at different vendors and barriers may have reduced phenotypic heterogeneity as a result of genetic variables, such as random genetic drift or population bottlenecks. Consistent with this hypothesis, we identified marked population structure among colonies from Harlan. Therefore, despite sharing the same name, investigators should be aware that important genetic and phenotypic differences exist among SD rats from different vendors or even from different colonies of the same vendor. If used judiciously this can be an asset to experimental design, but it can also be a pitfall for those unaware of the issue.

A cocaine context renews drug seeking preferentially in a subset of individuals.

Addiction is characterized by a high propensity for relapse, in part because cues associated with drugs can acquire Pavlovian incentive motivational properties, and acting as incentive stimuli, such cues can instigate and invigorate drug-seeking behavior. There is, however, considerable individual variation in the propensity to attribute incentive salience to reward cues. Discrete and localizable reward cues act as much more effective incentive stimuli in some rats (‘sign-trackers’, STs), than others (‘goal-trackers’, GTs). We asked whether similar individual variation exists for contextual cues associated with cocaine. Cocaine context conditioned motivation was quantified in two ways: (1) the ability of a cocaine context to evoke conditioned hyperactivity and (2) the ability of a context in which cocaine was previously self-administered to renew cocaine-seeking behavior. Finally, we assessed the effects of intra-accumbens core flupenthixol, a nonselective dopamine receptor antagonist, on context renewal. In contrast to studies using discrete cues, a cocaine context spurred greater conditioned hyperactivity, and more robustly renewed extinguished cocaine seeking in GTs than STs. In addition, cocaine context renewal was blocked by antagonism of dopamine receptors in the accumbens core. Thus, contextual cues associated with cocaine preferentially acquire motivational control over behavior in different individuals than do discrete cues, and in these individuals the ability of a cocaine context to create conditioned motivation for cocaine requires dopamine in the core of the nucleus accumbens. We speculate that different individuals may be preferentially sensitive to different ‘triggers’ of relapse.

Shedding Light on the Role of Ventral Tegmental Area Dopamine in Reward

Successful reward seeking requires the interaction of multiple psychological processes, including learning (i.e., creating connections between actions/stimuli and rewarding outcomes), motivation (i.e., wanting to obtain rewarding outcomes), and affect (i.e., liking rewarding outcomes). There are two